Harper's Illustrated Biochemistry-McGraw-Hill Medical (2003)

Metabolism of Unsaturated Fatty 23
Acids & Eicosanoids

Peter A. Mayes, PhD, DSc, & Kathleen M. Botham, PhD, DSc

BIOMEDICAL IMPORTANCE duced at the ∆4, ∆5, ∆6, and ∆9 positions (see Chapter
14) in most animals, but never beyond the ∆9 position.
Unsaturated fatty acids in phospholipids of the cell In contrast, plants are able to synthesize the nutrition-
membrane are important in maintaining membrane ally essential fatty acids by introducing double bonds at
fluidity. A high ratio of polyunsaturated fatty acids to the ∆12 and ∆15 positions.
saturated fatty acids (P:S ratio) in the diet is a major
factor in lowering plasma cholesterol concentrations 16 9 COOH
and is considered to be beneficial in preventing coro-
nary heart disease. Animal tissues have limited capacity Palmitoleic acid (ω7, 16:1, ∆9)
for desaturating fatty acids, and that process requires
certain dietary polyunsaturated fatty acids derived 18 9 COOH
from plants. These essential fatty acids are used to Oleic acid (ω 9, 18:1, ∆9)
form eicosanoic (C20) fatty acids, which in turn give
rise to the prostaglandins and thromboxanes and to 12 9 COOH
leukotrienes and lipoxins—known collectively as
eicosanoids. The prostaglandins and thromboxanes are 18
local hormones that are synthesized rapidly when re-
quired. Prostaglandins mediate inflammation, produce *Linoleic acid (ω 6, 18:2, ∆9,12)
pain, and induce sleep as well as being involved in the
regulation of blood coagulation and reproduction. 18 15 12 9 COOH
Nonsteroidal anti-inflammatory drugs such as aspirin
act by inhibiting prostaglandin synthesis. Leukotrienes *α-Linolenic acid (ω 3, 18:3, ∆9,12,15)
have muscle contractant and chemotactic properties
and are important in allergic reactions and inflamma- 14 11 8 5 COOH
tion.

SOME POLYUNSATURATED FATTY 20

ACIDS CANNOT BE SYNTHESIZED *Arachidonic acid (ω 6, 20:4, ∆5,8,11,14)

BY MAMMALS & ARE 20 17 14 11 8 5 COOH

NUTRITIONALLY ESSENTIAL Eicosapentaenoic acid (ω 3, 20:5, ∆5,8,11,14,17)

Certain long-chain unsaturated fatty acids of metabolic Figure 23–1. Structure of some unsaturated fatty
significance in mammals are shown in Figure 23–1. acids. Although the carbon atoms in the molecules are
Other C20, C22, and C24 polyenoic fatty acids may be conventionally numbered—ie, numbered from the car-
derived from oleic, linoleic, and α-linolenic acids by boxyl terminal—the ω numbers (eg, ω7 in palmitoleic
chain elongation. Palmitoleic and oleic acids are not es- acid) are calculated from the reverse end (the methyl
sential in the diet because the tissues can introduce a terminal) of the molecules. The information in paren-
double bond at the ∆9 position of a saturated fatty acid. theses shows, for instance, that α-linolenic acid con-
Linoleic and ␣-linolenic acids are the only fatty acids tains double bonds starting at the third carbon from
known to be essential for the complete nutrition of the methyl terminal, has 18 carbons and 3 double
many species of animals, including humans, and are bonds, and has these double bonds at the 9th, 12th,
known as the nutritionally essential fatty acids. In and 15th carbons from the carboxyl terminal. (Asterisks:
most mammals, arachidonic acid can be formed from Classified as “essential fatty acids.”)
linoleic acid (Figure 23–4). Double bonds can be intro-

190

METABOLISM OF UNSATURATED FATTY ACIDS & EICOSANOIDS / 191

Stearoyl CoA are able to synthesize the ω9 (oleic acid) family of unsat-
urated fatty acids completely by a combination of chain
O2 + NADH + H+ elongation and desaturation (Figure 23–3). However, as
indicated above, linoleic (ω6) or α-linolenic (ω3) acids
∆9 DESATURASE Cyt b5 required for the synthesis of the other members of the
ω6 or ω3 families must be supplied in the diet.
NAD++ 2H2O Linoleate may be converted to arachidonate via ␥-
Oleoyl CoA linolenate by the pathway shown in Figure 23–4. The
nutritional requirement for arachidonate may thus be
Figure 23–2. Microsomal ∆9 desaturase. dispensed with if there is adequate linoleate in the diet.
The desaturation and chain elongation system is greatly
MONOUNSATURATED FATTY diminished in the starving state, in response to glucagon
ACIDS ARE SYNTHESIZED BY and epinephrine administration, and in the absence of
A ⌬9 DESATURASE SYSTEM insulin as in type 1 diabetes mellitus.

Several tissues including the liver are considered to be re- DEFICIENCY SYMPTOMS ARE PRODUCED
sponsible for the formation of nonessential monounsatu-
rated fatty acids from saturated fatty acids. The first dou- WHEN THE ESSENTIAL FATTY ACIDS
ble bond introduced into a saturated fatty acid is nearly
always in the ∆9 position. An enzyme system—⌬9 desat- (EFA) ARE ABSENT FROM THE DIET
urase (Figure 23–2)—in the endoplasmic reticulum will
catalyze the conversion of palmitoyl-CoA or stearoyl-CoA Rats fed a purified nonlipid diet containing vitamins A
to palmitoleoyl-CoA or oleoyl-CoA, respectively. Oxygen and D exhibit a reduced growth rate and reproductive
and either NADH or NADPH are necessary for the reac- deficiency which may be cured by the addition of
tion. The enzymes appear to be similar to a monooxyge- linoleic, ␣-linolenic, and arachidonic acids to the diet.
nase system involving cytochrome b5 (Chapter 11). These fatty acids are found in high concentrations in
vegetable oils (Table 14–2) and in small amounts in ani-
SYNTHESIS OF POLYUNSATURATED mal carcasses. These essential fatty acids are required for
FATTY ACIDS INVOLVES DESATURASE prostaglandin, thromboxane, leukotriene, and lipoxin
& ELONGASE ENZYME SYSTEMS formation (see below), and they also have various other
functions which are less well defined. Essential fatty acids
Additional double bonds introduced into existing mo- are found in the structural lipids of the cell, often in the
nounsaturated fatty acids are always separated from each 2 position of phospholipids, and are concerned with the
other by a methylene group (methylene interrupted) ex- structural integrity of the mitochondrial membrane.
cept in bacteria. Since animals have a ∆9 desaturase, they
Arachidonic acid is present in membranes and ac-
counts for 5–15% of the fatty acids in phospholipids.
Docosahexaenoic acid (DHA; ω3, 22:6), which is syn-

ω9 Oleic acid 2 18:2 1 20:2 3 20:3 1 22:3 4 22:4
Family 18:1
Accumulates in essential
1 1 — fatty acid deficiency
24:1 22:1 1

20:1

ω6 Linoleic acid 2 18:3 1 20:3 3 20:4 1 22:4 4 22:5
Family 18:2

1 —
20:2

ω3 α-Linolenic 2 18:3 1 20:3 3 20:4 1 22:4 4 22:5
Family acid
18:3

Figure 23–3. Biosynthesis of the ω9, ω6, and ω3 families of polyunsaturated fatty

acids. Each step is catalyzed by the microsomal chain elongation or desaturase sys-
tem: 1, elongase; 2, ∆6 desaturase; 3, ∆5 desaturase; 4, ∆4 desaturase. ( — , Inhibition.)

192 / CHAPTER 23

12 9 O fatty acids in phospholipids, other complex lipids, and
C S CoA membranes, particularly with ∆5,8,11-eicosatrienoic acid
(ω9 20:3) (Figure 23–3). The triene:tetraene ratio in
18 plasma lipids can be used to diagnose the extent of es-
sential fatty acid deficiency.
Linoleoyl-CoA (∆9,12-octadecadienoyl-CoA)
Trans Fatty Acids Are Implicated
O2 + NADH + H+ ∆6 in Various Disorders
2H2O + NAD+ DESATURASE
Small amounts of trans-unsaturated fatty acids are found
12 9 6 in ruminant fat (eg, butter fat has 2–7%), where they
arise from the action of microorganisms in the rumen,
18 C S CoA but the main source in the human diet is from partially
O hydrogenated vegetable oils (eg, margarine). Trans fatty
acids compete with essential fatty acids and may exacer-
γ-Linolenoyl-CoA (∆6,9,12-octadecatrienoyl-CoA) bate essential fatty acid deficiency. Moreover, they are
structurally similar to saturated fatty acids (Chapter 14)
C2 MICROSOMAL CHAIN and have comparable effects in the promotion of hyper-
(Malonyl-CoA, ELONGATION SYSTEM cholesterolemia and atherosclerosis (Chapter 26).

NADPH) (ELONGASE) EICOSANOIDS ARE FORMED FROM C20
POLYUNSATURATED FATTY ACIDS
14 11 8
Arachidonate and some other C20 polyunsaturated fatty
20 C S CoA acids give rise to eicosanoids, physiologically and phar-
macologically active compounds known as prosta-
O glandins (PG), thromboxanes (TX), leukotrienes
Dihomo-γ-linolenoyl-CoA (∆8,11,14-eicosatrienoyl-CoA) (LT), and lipoxins (LX) (Chapter 14). Physiologically,
they are considered to act as local hormones function-
O2 + NADH + H+ ∆5 ing through G-protein-linked receptors to elicit their
2H2O + NAD+ DESATURASE biochemical effects.

14 11 8 5 O There are three groups of eicosanoids that are syn-
C S CoA thesized from C20 eicosanoic acids derived from the es-
sential fatty acids linoleate and ␣-linolenate, or di-
20 rectly from dietary arachidonate and eicosapentaenoate
(Figure 23–5). Arachidonate, usually derived from the
Arachidonoyl-CoA (∆5,8,11,14-eicosatetraenoyl-CoA) 2 position of phospholipids in the plasma membrane by
the action of phospholipase A2 (Figure 24–6)—but also
Figure 23–4. Conversion of linoleate to arachido- from the diet—is the substrate for the synthesis of the
PG2, TX2 series (prostanoids) by the cyclooxygenase
nate. Cats cannot carry out this conversion owing to ab- pathway, or the LT4 and LX4 series by the lipoxyge-
sence of ∆6 desaturase and must obtain arachidonate in nase pathway, with the two pathways competing for
their diet. the arachidonate substrate (Figure 23–5).

thesized from α-linolenic acid or obtained directly from THE CYCLOOXYGENASE
fish oils, is present in high concentrations in retina, PATHWAY IS RESPONSIBLE FOR
cerebral cortex, testis, and sperm. DHA is particularly PROSTANOID SYNTHESIS
needed for development of the brain and retina and is
supplied via the placenta and milk. Patients with retini- Prostanoid synthesis (Figure 23–6) involves the con-
tis pigmentosa are reported to have low blood levels of sumption of two molecules of O2 catalyzed by
DHA. In essential fatty acid deficiency, nonessential prostaglandin H synthase (PGHS), which consists of
polyenoic acids of the ω9 family replace the essential two enzymes, cyclooxygenase and peroxidase. PGHS
is present as two isoenzymes, PGHS-1 and PGHS-2.
The product, an endoperoxide (PGH), is converted to
prostaglandins D, E, and F as well as to a thromboxane

METABOLISM OF UNSATURATED FATTY ACIDS & EICOSANOIDS / 193

Diet Membrane phospholipid

Linoleate PHOSPHOLIPASE + Angiotensin II
–2H A2 Bradykinin
Epinephrine
Thrombin

γ-Linolenate GROUP 1 Diet GROUP 2
+2C
Prostanoids COOH Prostanoids
PGE1
1 PGF1 5,8,11,14- PGD2
TXA1 Eicosatetraenoate 1 PGE2

COOH –2H Arachidonate PGF2
PGI2
Leukotrienes TXA2

LTA3 Leukotrienes Lipoxins
LTC3
8,11,14-Eicosatrienoate 2 LTD3 LTA4 LXA4
(dihomo γ-linolenate) 2 LTB4 LXB4
LXC4
LTC4 LXD4
LTD4 LXE4
LTE4

1 GROUP 3

–2H COOH Prostanoids
Eicosatetraenoate
5,8,11,14,17- 2 PGD3
+2C Eicosapentaenoate PGE3
Octadecatetraenoate PGF3
PGI3
TXA3

Leukotrienes

LTA5
LTB5
LTC5

–2H Diet
α-Linolenate

Diet

Figure 23–5. The three groups of eicosanoids and their biosynthetic origins. (PG, prostaglandin; PGI, prosta-
cyclin; TX, thromboxane; LT, leukotriene; LX, lipoxin; ᭺1 , cyclooxygenase pathway; ᭺2 , lipoxygenase pathway.)
The subscript denotes the total number of double bonds in the molecule and the series to which the compound
belongs.

(TXA2) and prostacyclin (PGI2). Each cell type pro- Essential Fatty Acids Do Not Exert
duces only one type of prostanoid. Aspirin, a nons- All Their Physiologic Effects Via
teroidal anti-inflammatory drug (NSAID), inhibits cy- Prostaglandin Synthesis
clooxygenase of both PGHS-1 and PGHS-2 by
acetylation. Most other NSAIDs, such as indomethacin The role of essential fatty acids in membrane formation
and ibuprofen, inhibit cyclooxygenases by competing is unrelated to prostaglandin formation. Prostaglandins
with arachidonate. Transcription of PGHS-2—but not do not relieve symptoms of essential fatty acid defi-
of PGHS-1—is completely inhibited by anti-inflam- ciency, and an essential fatty acid deficiency is not
matory corticosteroids. caused by inhibition of prostaglandin synthesis.

194 / CHAPTER 23

COOH

Arachidonate *

2O2 CYCLOOXYGENASE Aspirin

– Indomethacin

COOH O Ibuprofen
COOH

PGI2 O OOH * O
O PGG2
PROSTACYCLIN PEROXIDASE
SYNTHASE
O COOH CH COOH
+
O
ISOMERASE CH

OH OH OH O OH
PGH2 Malondialdehyde + HHT

O COOH THROMBOXANE Imidazole
O SYNTHASE
O –

OH OH OH OH COOH O COOH
6-Keto PGF1α PGE2 OH O OH TXA2

OH REDUCTASE ISOMERASE OH

COOH COOH COOH
O HO
O

OH OH OH OH
PGF2 α PGD2 TXB2

Figure 23–6. Conversion of arachidonic acid to prostaglandins and thromboxanes of series 2. (PG,
prostaglandin; TX, thromboxane; PGI, prostacyclin; HHT, hydroxyheptadecatrienoate.) (Asterisk: Both of these
starred activities are attributed to one enzyme: prostaglandin H synthase. Similar conversions occur in
prostaglandins and thromboxanes of series 1 and 3.)

Cyclooxygenase Is a “Suicide Enzyme” nase pathway in response to both immunologic and
nonimmunologic stimuli. Three different lipoxygenases
“Switching off” of prostaglandin activity is partly achieved (dioxygenases) insert oxygen into the 5, 12, and 15 po-
by a remarkable property of cyclooxygenase—that of sitions of arachidonic acid, giving rise to hydroperox-
self-catalyzed destruction; ie, it is a “suicide enzyme.” ides (HPETE). Only 5-lipoxygenase forms leuko-
Furthermore, the inactivation of prostaglandins by 15- trienes (details in Figure 23–7). Lipoxins are a family of
hydroxyprostaglandin dehydrogenase is rapid. Block- conjugated tetraenes also arising in leukocytes. They are
ing the action of this enzyme with sulfasalazine or in- formed by the combined action of more than one
domethacin can prolong the half-life of prostaglandins lipoxygenase (Figure 23–7).
in the body.
CLINICAL ASPECTS
LEUKOTRIENES & LIPOXINS
ARE FORMED BY THE Symptoms of Essential Fatty Acid
LIPOXYGENASE PATHWAY Deficiency in Humans Include Skin
Lesions & Impairment of Lipid Transport
The leukotrienes are a family of conjugated trienes
formed from eicosanoic acids in leukocytes, mastocy- In adults subsisting on ordinary diets, no signs of es-
toma cells, platelets, and macrophages by the lipoxyge- sential fatty acid deficiencies have been reported. How-

METABOLISM OF UNSATURATED FATTY ACIDS & EICOSANOIDS / 195

COOH

12-LIPOXYGENASE 15-LIPOXYGENASE
COOH
Arachidonate COOH
1
HOO O2
HO
12-HPETE OOH
1 15-HPETE

5-LIPOXYGENASE COOH

COOH OH
15-HETE

OOH OH
5-HETE
12-HETE COOH COOH

5-LIPOXYGENASE

5-HPETE 1

OH H2O OH OH
COOH O COOH
COOH
OH
Leukotriene B4 H2O

2 15-LIPOXYGENASE OH
3 Lipoxins, eg, LXA4
Leukotriene A4
Glutathione

Glutamic acid

O NH2
OH
Glycine Glycine
O O NH2
O NH NH2
HO NH NH HO
HO
O S Cysteine Glutamic acid Cysteine Glycine OS Cysteine
OS

COOH 4 COOH 5 COOH
OH OH
OH

Leukotriene C4 Leukotriene D4 Leukotriene E4

Figure 23–7. Conversion of arachidonic acid to leukotrienes and lipoxins of series 4 via the lipoxygenase path-

way. Some similar conversions occur in series 3 and 5 leukotrienes. (HPETE, hydroperoxyeicosatetraenoate; HETE,

hydroxyeicosatetraenoate; ᭺1 , peroxidase; ᭺2 , leukotriene A4 epoxide hydrolase; ᭺3 , glutathione S-transferase;
᭺4 , γ-glutamyltranspeptidase; ᭺5 , cysteinyl-glycine dipeptidase.)

ever, infants receiving formula diets low in fat and pa- Abnormal Metabolism of Essential Fatty
tients maintained for long periods exclusively by intra- Acids Occurs in Several Diseases
venous nutrition low in essential fatty acids show defi-
ciency symptoms that can be prevented by an essential Abnormal metabolism of essential fatty acids, which
fatty acid intake of 1–2% of the total caloric require- may be connected with dietary insufficiency, has been
ment. noted in cystic fibrosis, acrodermatitis enteropathica,

196 / CHAPTER 23 immediate hypersensitivity reactions, such as asthma.
Leukotrienes are vasoactive, and 5-lipoxygenase has
hepatorenal syndrome, Sjögren-Larsson syndrome, been found in arterial walls. Evidence supports a role
multisystem neuronal degeneration, Crohn’s disease, for lipoxins in vasoactive and immunoregulatory func-
cirrhosis and alcoholism, and Reye’s syndrome. Ele- tion, eg, as counterregulatory compounds (chalones) of
vated levels of very long chain polyenoic acids have the immune response.
been found in the brains of patients with Zellweger’s
syndrome (Chapter 22). Diets with a high P:S (polyun- SUMMARY
saturated:saturated fatty acid) ratio reduce serum cho-
lesterol levels and are considered to be beneficial in • Biosynthesis of unsaturated long-chain fatty acids is
terms of the risk of development of coronary heart dis- achieved by desaturase and elongase enzymes, which
ease. introduce double bonds and lengthen existing acyl
chains, respectively.
Prostanoids Are Potent Biologically
Active Substances • Higher animals have ∆4, ∆5, ∆6, and ∆9 desaturases
but cannot insert new double bonds beyond the 9
Thromboxanes are synthesized in platelets and upon position of fatty acids. Thus, the essential fatty acids
release cause vasoconstriction and platelet aggregation. linoleic (ω6) and α-linolenic (ω3) must be obtained
Their synthesis is specifically inhibited by low-dose as- from the diet.
pirin. Prostacyclins (PGI2) are produced by blood ves-
sel walls and are potent inhibitors of platelet aggrega- • Eicosanoids are derived from C20 (eicosanoic) fatty
tion. Thus, thromboxanes and prostacyclins are acids synthesized from the essential fatty acids and
antagonistic. PG3 and TX3, formed from eicosapen- comprise important groups of physiologically and
taenoic acid (EPA) in fish oils, inhibit the release of pharmacologically active compounds, including the
arachidonate from phospholipids and the formation prostaglandins, thromboxanes, leukotrienes, and
of PG2 and TX2. PGI3 is as potent an antiaggregator of lipoxins.
platelets as PGI2, but TXA3 is a weaker aggregator than
TXA2, changing the balance of activity and favoring REFERENCES
longer clotting times. As little as 1 ng/mL of plasma
prostaglandins causes contraction of smooth muscle in Connor WE: The beneficial effects of omega-3 fatty acids: cardio-
animals. Potential therapeutic uses include prevention vascular disease and neurodevelopment. Curr Opin Lipidol
of conception, induction of labor at term, termination 1997;8:1.
of pregnancy, prevention or alleviation of gastric ulcers,
control of inflammation and of blood pressure, and re- Fischer S: Dietary polyunsaturated fatty acids and eicosanoid for-
lief of asthma and nasal congestion. In addition, PGD2 mation in humans. Adv Lipid Res 1989;23:169.
is a potent sleep-promoting substance. Prostaglandins
increase cAMP in platelets, thyroid, corpus luteum, Lagarde M, Gualde N, Rigaud M: Metabolic interactions between
fetal bone, adenohypophysis, and lung but reduce eicosanoids in blood and vascular cells. Biochem J 1989;
cAMP in renal tubule cells and adipose tissue (Chap- 257:313.
ter 25).
Neuringer M, Anderson GJ, Connor WE: The essentiality of n-3
Leukotrienes & Lipoxins Are Potent fatty acids for the development and function of the retina and
Regulators of Many Disease Processes brain. Annu Rev Nutr 1988;8:517.

Slow-reacting substance of anaphylaxis (SRS-A) is a Serhan CN: Lipoxin biosynthesis and its impact in inflammatory
mixture of leukotrienes C4, D4, and E4. This mixture of and vascular events. Biochim Biophys Acta 1994;1212:1.
leukotrienes is a potent constrictor of the bronchial air-
way musculature. These leukotrienes together with Smith WL, Fitzpatrick FA: The eicosanoids: Cyclooxygenase,
leukotriene B4 also cause vascular permeability and at- lipoxygenase, and epoxygenase pathways. In: Biochemistry of
traction and activation of leukocytes and are important Lipids, Lipoproteins and Membranes. Vance DE, Vance JE
regulators in many diseases involving inflammatory or (editors). Elsevier, 1996.

Tocher DR, Leaver MJ, Hodgson PA: Recent advances in the bio-
chemistry and molecular biology of fatty acyl desaturases.
Prog Lipid Res 1998;37:73.

Valenzuela A, Morgado N: Trans fatty acid isomers in human
health and the food industry. Biol Res 1999;32:273.

Metabolism of Acylglycerols 24
& Sphingolipids

Peter A. Mayes, PhD, DSc, & Kathleen M. Botham, PhD, DSc

BIOMEDICAL IMPORTANCE possess glycerol kinase, found in significant amounts
in liver, kidney, intestine, brown adipose tissue, and
Acylglycerols constitute the majority of lipids in the lactating mammary gland.
body. Triacylglycerols are the major lipids in fat de-
posits and in food, and their roles in lipid transport and TRIACYLGLYCEROLS &
storage and in various diseases such as obesity, diabetes, PHOSPHOGLYCEROLS ARE FORMED BY
and hyperlipoproteinemia will be described in subse- ACYLATION OF TRIOSE PHOSPHATES
quent chapters. The amphipathic nature of phospho-
lipids and sphingolipids makes them ideally suitable as The major pathways of triacylglycerol and phosphoglyc-
the main lipid component of cell membranes. Phos- erol biosynthesis are outlined in Figure 24–1. Impor-
pholipids also take part in the metabolism of many tant substances such as triacylglycerols, phosphatidyl-
other lipids. Some phospholipids have specialized func- choline, phosphatidylethanolamine, phosphatidylinositol,
tions; eg, dipalmitoyl lecithin is a major component of and cardiolipin, a constituent of mitochondrial mem-
lung surfactant, which is lacking in respiratory distress branes, are formed from glycerol-3-phosphate. Significant
syndrome of the newborn. Inositol phospholipids in the branch points in the pathway occur at the phosphati-
cell membrane act as precursors of hormone second date and diacylglycerol steps. From dihydroxyacetone
messengers, and platelet-activating factor is an alkyl- phosphate are derived phosphoglycerols containing an
phospholipid. Glycosphingolipids, containing sphingo- ether link (COC), the best-known of which
sine and sugar residues as well as fatty acid and found in are plasmalogens and platelet-activating factor (PAF).
the outer leaflet of the plasma membrane with their Glycerol 3-phosphate and dihydroxyacetone phosphate
oligosaccharide chains facing outward, form part of the are intermediates in glycolysis, making a very important
glycocalyx of the cell surface and are important (1) in connection between carbohydrate and lipid metabo-
cell adhesion and cell recognition; (2) as receptors for lism.
bacterial toxins (eg, the toxin that causes cholera); and
(3) as ABO blood group substances. A dozen or so gly- Glycerol 3-phosphate Dihydroxyacetone phosphate
colipid storage diseases have been described (eg,
Gaucher’s disease, Tay-Sachs disease), each due to a ge-
netic defect in the pathway for glycolipid degradation
in the lysosomes.

HYDROLYSIS INITIATES CATABOLISM Phosphatidate Plasmalogens PAF

OF TRIACYLGLYCEROLS Diacylglycerol Cardiolipin Phosphatidylinositol

Triacylglycerols must be hydrolyzed by a lipase to their Phosphatidylcholine Triacylglycerol Phosphatidylinositol
constituent fatty acids and glycerol before further catab-
olism can proceed. Much of this hydrolysis (lipolysis) Phosphatidylethanolamine 4,5-bisphosphate
occurs in adipose tissue with release of free fatty acids
into the plasma, where they are found combined with Figure 24–1. Overview of acylglycerol biosynthesis.
serum albumin. This is followed by free fatty acid up- (PAF, platelet-activating factor.)
take into tissues (including liver, heart, kidney, muscle,
lung, testis, and adipose tissue, but not readily by
brain), where they are oxidized or reesterified. The uti-
lization of glycerol depends upon whether such tissues

197

ATP ADP NAD+ NADH + H+

H 2C OH H 2C OH H 2C OH Glycolysis
HO C H
GLYCEROL KINASE HO C H GLYCEROL- CO
H 2C OH 3-PHOSPHATE
Glycerol H2C O P DEHYDROGENASE H2C O P
sn-Glycerol Dihydroxyacetone
3-phosphate
phosphate

Acyl-CoA (mainly saturated)

GLYCEROL-
2 3-PHOSPHATE

ACYLTRANSFERASE

H 2C OH CoA
R2 C O C H
O
O H 2C OH H 2C O C R1
2-Monoacylglycerol HO CH

H2C O P
1-Acylglycerol-

3-phosphate
(lysophosphatidate)

Acyl-CoA (usually unsaturated)

Acyl-CoA 1 1-ACYLGLYCEROL-
3-PHOSPHATE
MONOACYLGLYCEROL
ACYLTRANSFERASE ACYLTRANSFERASE
(INTESTINE)
CoA
CoA
O
H 2C O C R1
R2 C O C H

O H2C O P

1,2-Diacylglycerol
phosphate

(phosphatidate)

Choline H 2O CTP

ATP PHOSPHATIDATE CDP-DG
PHOSPHOHYDROLASE SYNTHASE
CHOLINE
KINASE

ADP P1 PP 1
Phosphocholine O O
H 2C O C R1
CTP R2 C O C H H 2C O C R1
O H 2COH
CTP: 1,2-Diacylglycerol R2 C O C H P
PHOSPHOCHOLINE O H2C O P
Acyl-CoA
CYTIDYL Cytidine Cardiolipin
TRANSFERASE CDP-diacylglycerol

PP1 Inositol
CDP-choline

CDP-CHOLINE: DIACYLGLYCEROL PHOSPHATIDYL-
DIACYLGLYCEROL ACYLTRANSFERASE INOSITOL SYNTHASE
PHOSPHOCHOLINE
CoA CMP ATP ADP
TRANSFERASE O O
KINASE O
CMP

O

H 2C O C R1 H 2C O C R1 H 2C O C R1 H 2C O C R1

R2 C O C H R2 C O C H O R2 C O C H R2 C O C H

O H2C O P O H 2C O C R3 O H2C O P O H 2C O P Inositol P
Choline Triacyglycerol Inositol Phosphatidylinositol 4-phosphate

Phosphatidylcholine Phosphatidylinositol ATP

PHOSPHATIDYLETHANOLAMINE (–CH3)3 KINASE
N-METHYLTRANSFERASE Serine

Phosphatidylethanolamine ADP O
CO2 H 2C O C R1
R2 C OC H
Phosphatidylserine Ethanolamine O H 2C O P Inositol

Figure 24–2 . Biosynthesis of triacylglycerol and phospholipids. P
(᭺1 , Monoacylglycerol pathway; ᭺2 , glycerol phosphate pathway.)
P
Phosphatidylethanolamine may be formed from ethanolamine by a Phosphatidylinositol 4,5-bisphosphate

pathway similar to that shown for the formation of phosphatidyl-

choline from choline.

METABOLISM OF ACYLGLYCEROLS & SPHINGOLIPIDS / 199

Phosphatidate Is the Common Precursor from phosphatidylglycerol, which in turn is synthesized
from CDP-diacylglycerol (Figure 24–2) and glycerol
in the Biosynthesis of Triacylglycerols, 3-phosphate according to the scheme shown in Figure
24–3. Cardiolipin, found in the inner membrane of
Many Phosphoglycerols, & Cardiolipin mitochondria, is specifically required for the function-
ing of the phosphate transporter and for cytochrome
Both glycerol and fatty acids must be activated by ATP oxidase activity.
before they can be incorporated into acylglycerols.
Glycerol kinase catalyzes the activation of glycerol to B. BIOSYNTHESIS OF GLYCEROL ETHER PHOSPHOLIPIDS
sn-glycerol 3-phosphate. If the activity of this enzyme is
absent or low, as in muscle or adipose tissue, most of This pathway is located in peroxisomes. Dihydroxyace-
the glycerol 3-phosphate is formed from dihydroxyace- tone phosphate is the precursor of the glycerol moiety
tone phosphate by glycerol-3-phosphate dehydrogen- of glycerol ether phospholipids (Figure 24–4). This
ase (Figure 24–2). compound combines with acyl-CoA to give 1-acyldihy-
droxyacetone phosphate. The ether link is formed in
A. BIOSYNTHESIS OF TRIACYLGLYCEROLS the next reaction, producing 1-alkyldihydroxyacetone
phosphate, which is then converted to 1-alkylglycerol
Two molecules of acyl-CoA, formed by the activation 3-phosphate. After further acylation in the 2 position,
of fatty acids by acyl-CoA synthetase (Chapter 22), the resulting 1-alkyl-2-acylglycerol 3-phosphate (analo-
combine with glycerol 3-phosphate to form phosphati- gous to phosphatidate in Figure 24–2) is hydrolyzed to
date (1,2-diacylglycerol phosphate). This takes place in give the free glycerol derivative. Plasmalogens, which
two stages, catalyzed by glycerol-3-phosphate acyl- comprise much of the phospholipid in mitochondria,
transferase and 1-acylglycerol-3-phosphate acyltrans- are formed by desaturation of the analogous 3-phos-
ferase. Phosphatidate is converted by phosphatidate phoethanolamine derivative (Figure 24–4). Platelet-
phosphohydrolase and diacylglycerol acyltransferase activating factor (PAF) (1-alkyl-2-acetyl-sn-glycerol-3-
to 1,2-diacylglycerol and then triacylglycerol. In intesti- phosphocholine) is synthesized from the corresponding
nal mucosa, monoacylglycerol acyltransferase con- 3-phosphocholine derivative. It is formed by many
verts monoacylglycerol to 1,2-diacylglycerol in the blood cells and other tissues and aggregates platelets at
monoacylglycerol pathway. Most of the activity of concentrations as low as 10−11 mol/L. It also has hy-
these enzymes resides in the endoplasmic reticulum of potensive and ulcerogenic properties and is involved in
the cell, but some is found in mitochondria. Phosphati- a variety of biologic responses, including inflammation,
date phosphohydrolase is found mainly in the cytosol, chemotaxis, and protein phosphorylation.
but the active form of the enzyme is membrane-bound.
CDP-Diacyl- sn-Glycerol
In the biosynthesis of phosphatidylcholine and glycerol 3-phosphate
phosphatidylethanolamine (Figure 24–2), choline or
ethanolamine must first be activated by phosphoryla- CMP
tion by ATP followed by linkage to CTP. The resulting Phosphatidylglycerol phosphate
CDP-choline or CDP-ethanolamine reacts with 1,2-di-
acylglycerol to form either phosphatidylcholine or H2O
phosphatidylethanolamine, respectively. Phosphatidyl-
serine is formed from phosphatidylethanolamine di- Pi
rectly by reaction with serine (Figure 24–2). Phos- Phosphatidylglycerol
phatidylserine may re-form phosphatidylethanolamine
by decarboxylation. An alternative pathway in liver en- CMP
ables phosphatidylethanolamine to give rise directly to
phosphatidylcholine by progressive methylation of the Cardiolipin
ethanolamine residue. In spite of these sources of (diphosphatidylglycerol)
choline, it is considered to be an essential nutrient in
many mammalian species, but this has not been estab- Figure 24–3. Biosynthesis of cardiolipin.
lished in humans.

The regulation of triacylglycerol, phosphatidyl-
choline, and phosphatidylethanolamine biosynthesis is
driven by the availability of free fatty acids. Those that
escape oxidation are preferentially converted to phos-
pholipids, and when this requirement is satisfied they
are used for triacylglycerol synthesis.

A phospholipid present in mitochondria is cardio-
lipin (diphosphatidylglycerol; Figure 14–8). It is formed

200 / CHAPTER 24

Acyl-CoA O R2 (CH2)2 OH NADPH
H2COH + H+ NADP+

H2C O C R1 H2C O (CH2)2 R2 H2C O (CH2)2 R2

OC OC OC HO C H

H2C O P ACYL- H2C O P SYNTHASE H2C O P REDUCTASE H2C O P
TRANSFERASE

HOOC R1

Dihydroxyacetone 1-Acyldihydroxyacetone 1-Alkyldihydroxyacetone 1-Alkylglycerol 3-phosphate
phosphate phosphate phosphate Acyl-CoA

ACYL- *

TRANSFERASE

CDP- Pi H2O
CMP Ethanolamine

O H2C O (CH2)2 R2 O H2C O (CH2)2 R2 O H2C O (CH2)2 R2

R3 C O C H R3 C O C H R3 C O C H

H2C O P CH2 CH2 NH2 CDP-ETHANOLAMINE: H2C OH PHOSPHOHYDROLASE H2C O P
ALKYLACYLGLYCEROL
1-Alkyl-2-acylglycerol
3-phosphoethanolamine PHOSPHOETHANOLAMINE

TRANSFERASE 1-Alkyl-2-acylglycerol 3-phosphate

1-Alkyl-2-acylglycerol

NADPH, O2, CDP-choline
Cyt b5
DESATURASE CDP-CHOLINE:
ALKYLACYLGLYCEROL
Alkyl, diacyl glycerols
PHOSPHOCHOLINE
TRANSFERASE

O H2C O CH CH R2 CMP
R3 C O C H
O H2C O (CH2)2 R2 H2O R3 COOH
H2C O P (CH2)2 NH2
R3 C O C H H2C O (CH2)2 R2
1-Alkenyl-2-acylglycerol
3-phosphoethanolamine H2C O P HO C H P
Choline PHOSPHOLIPASE A2 H2C O
plasmalogen
1-Alkyl-2-acylglycerol Choline
3-phosphocholine 1-Alkyl-2-lysoglycerol
Acetyl-CoA 3-phosphocholine

ACETYLTRANSFERASE

O H2C O (CH2)2 R2
H3C C O C H

H2C O P

Choline

1-Alkyl-2-acetylglycerol 3-phosphocholine
PAF

Figure 24–4. Biosynthesis of ether lipids, including plasmalogens, and platelet-activating factor (PAF). In the
de novo pathway for PAF synthesis, acetyl-CoA is incorporated at stage *, avoiding the last two steps in the path-
way shown here.

Phospholipases Allow Degradation solecithin) is attacked by lysophospholipase, forming
& Remodeling of Phosphoglycerols the corresponding glyceryl phosphoryl base, which in
turn may be split by a hydrolase liberating glycerol
Although phospholipids are actively degraded, each 3-phosphate plus base. Phospholipases A1, A2, B, C,
portion of the molecule turns over at a different rate— and D attack the bonds indicated in Figure 24–6.
eg, the turnover time of the phosphate group is differ- Phospholipase A2 is found in pancreatic fluid and
ent from that of the 1-acyl group. This is due to the snake venom as well as in many types of cells; phos-
presence of enzymes that allow partial degradation fol- pholipase C is one of the major toxins secreted by bac-
lowed by resynthesis (Figure 24–5). Phospholipase A2 teria; and phospholipase D is known to be involved in
catalyzes the hydrolysis of glycerophospholipids to form mammalian signal transduction.
a free fatty acid and lysophospholipid, which in turn
may be reacylated by acyl-CoA in the presence of an Lysolecithin (lysophosphatidylcholine) may be
acyltransferase. Alternatively, lysophospholipid (eg, ly- formed by an alternative route that involves lecithin:
cholesterol acyltransferase (LCAT). This enzyme,

METABOLISM OF ACYLGLYCEROLS & SPHINGOLIPIDS / 201

O found in plasma, catalyzes the transfer of a fatty acid
O H2C O C R1 residue from the 2 position of lecithin to cholesterol to
R2 C O C H form cholesteryl ester and lysolecithin and is considered
to be responsible for much of the cholesteryl ester in
H2C O P Choline plasma lipoproteins. Long-chain saturated fatty acids
Phosphatidylcholine are found predominantly in the 1 position of phospho-
lipids, whereas the polyunsaturated acids (eg, the pre-
H2O cursors of prostaglandins) are incorporated more into
the 2 position. The incorporation of fatty acids into
ACYLTRANSFERASE PHOSPHOLIPASE A2 lecithin occurs by complete synthesis of the phospho-
lipid, by transacylation between cholesteryl ester and
R2 COOH lysolecithin, and by direct acylation of lysolecithin by
acyl-CoA. Thus, a continuous exchange of the fatty
O acids is possible, particularly with regard to introducing
essential fatty acids into phospholipid molecules.
Acyl-CoA H2C O C R1
HO C H ALL SPHINGOLIPIDS ARE FORMED

H2C O P Choline FROM CERAMIDE
Lysophosphatidylcholine (lysolecithin)
Ceramide is synthesized in the endoplasmic reticulum
H2O from the amino acid serine according to Figure 24–7.
Ceramide is an important signaling molecule (second
LYSOPHOSPHOLIPASE messenger) regulating pathways including apoptosis
(processes leading to cell death), cell senescence, and
R1 COOH differentiation, and opposes some of the actions of di-
H2C OH acylglycerol.

HO C H Sphingomyelins (Figure 14–11) are phospholipids
H2C O P Choline and are formed when ceramide reacts with phos-
phatidylcholine to form sphingomyelin plus diacylglyc-
Glycerylphosphocholine erol (Figure 24–8A). This occurs mainly in the Golgi
apparatus and to a lesser extent in the plasma mem-
H2O brane.

GLYCERYLPHOSPHO- Glycosphingolipids Are a Combination
CHOLINE HYDROLASE of Ceramide With One or More
Sugar Residues
H2C OH + Choline
HO C H The simplest glycosphingolipids (cerebrosides) are
galactosylceramide (GalCer) and glucosylceramide
H2C O P (GlcCer). GalCer is a major lipid of myelin, whereas
GlcCer is the major glycosphingolipid of extraneural
sn-Glycerol 3-phosphate tissues and a precursor of most of the more complex
glycosphingolipids. Galactosylceramide (Figure 24–8B)
Figure 24–5. Metabolism of phosphatidylcholine is formed in a reaction between ceramide and UDPGal
(lecithin). (formed by epimerization from UDPGlc—Figure
20–6). Sulfogalactosylceramide and other sulfolipids
PHOSPHOLIPASE B PHOSPHOLIPASE A1 such as the sulfo(galacto)-glycerolipids and the
O steroid sulfates are formed after further reactions in-
volving 3′-phosphoadenosine-5′-phosphosulfate (PAPS;
O H2C O C R1 “active sulfate”). Gangliosides are synthesized from
ceramide by the stepwise addition of activated sugars (eg,
PHOSPHOLIPASE D UDPGlc and UDPGal) and a sialic acid, usually N-
R2 C O C H O acetylneuraminic acid (Figure 24–9). A large number
of gangliosides of increasing molecular weight may be
H2C O P O N-BASE formed. Most of the enzymes transferring sugars from

PHOSPHOLIPASE A2 O–

PHOSPHOLIPASE C

Figure 24–6. Sites of the hydrolytic activity of phos-
pholipases on a phospholipid substrate.

202 / CHAPTER 24 −OOC +NH3 OH nucleotide sugars (glycosyl transferases) are found in
the Golgi apparatus.
O CH CH2
CH3 (CH2)14 C S CoA Serine Glycosphingolipids are constituents of the outer
leaflet of plasma membranes and are important in cell
Palmitoyl-CoA adhesion and cell recognition. Some are antigens, eg,
ABO blood group substances. Certain gangliosides
Pyridoxal phosphate, Mn2+ function as receptors for bacterial toxins (eg, for cholera
toxin, which subsequently activates adenylyl cyclase).
CoA SH SERINE
PALMITOYLTRANSFERASE CLINICAL ASPECTS

CO2 Deficiency of Lung Surfactant Causes
Respiratory Distress Syndrome
O
Lung surfactant is composed mainly of lipid with
CH3 (CH2)12 CH2 CH2 C CH CH2 OH some proteins and carbohydrate and prevents the alve-
oli from collapsing. Surfactant activity is largely attrib-
NH3+ uted to dipalmitoylphosphatidylcholine, which is
3-Ketosphinganine synthesized shortly before parturition in full-term in-
fants. Deficiency of lung surfactant in the lungs of
NADPH + H+ many preterm newborns gives rise to respiratory dis-
tress syndrome. Administration of either natural or ar-
3-KETOSPHINGANINE tificial surfactant has been of therapeutic benefit.
REDUCTASE
Phospholipids & Sphingolipids
NADP+ Are Involved in Multiple Sclerosis
and Lipidoses
CH3(CH2)12 CH2 CH2 CH CH CH2 OH
Certain diseases are characterized by abnormal quanti-
OH NH3+ ties of these lipids in the tissues, often in the nervous
Dihydrosphingosine (sphinganine) system. They may be classified into two groups: (1) true
demyelinating diseases and (2) sphingolipidoses.
R CO S CoA DIHYDROSPHINGOSINE
Acyl-CoA N -ACYLTRANSFERASE In multiple sclerosis, which is a demyelinating dis-
ease, there is loss of both phospholipids (particularly
CoA SH ethanolamine plasmalogen) and of sphingolipids from
CH3 (CH2)12 CH2 CH2 CH CH CH2 OH white matter. Thus, the lipid composition of white
matter resembles that of gray matter. The cerebrospinal
OH NH CO R fluid shows raised phospholipid levels.
Dihydroceramide
The sphingolipidoses (lipid storage diseases) are a
DIHYDROCERAMIDE group of inherited diseases that are often manifested in
2H DESATURASE childhood. These diseases are part of a larger group of
lysosomal disorders and exhibit several constant fea-
CH3 (CH2)12 CH CH CH CH CH2 OH tures: (1) Complex lipids containing ceramide accumu-
OH NH CO R late in cells, particularly neurons, causing neurodegen-

Ceramide

Figure 24–7. Biosynthesis of ceramide.

A Ceramide Sphingomyelin

Phosphatidylcholine Diacylglycerol

Figure 24–8. Biosynthesis of sphingomyelin (A),

UDPGal UDP PAPS Sulfogalactosyl- galactosylceramide and its sulfo derivative (B). (PAPS,

Galactosylceramide ceramide “active sulfate,” adenosine 3′-phosphate-5′-phospho-

B Ceramide (cerebroside) (sulfatide) sulfate.)

METABOLISM OF ACYLGLYCEROLS & SPHINGOLIPIDS / 203

UDPGlc UDP UDPGal UDP CMP-NeuAc CMP
Ceramide
Glucosyl Cer-Glc-Gal Cer-Glc-Gal
ceramide
(Cer-Glc) NeuAc
(GM3)

UDP-N-acetyl
galactosamine

UDP UDPGal UDP

Higher gangliosides Cer-Glc-Gal-GalNAc-Gal Cer-Glc-Gal-GalNAc
(disialo- and trisialo-
NeuAc NeuAc
gangliosides) (GM1) (GM2)

Figure 24–9. Biosynthesis of gangliosides. (NeuAc, N-acetylneuraminic acid.)

eration and shortening the life span. (2) The rate of dase) in the treatment of Gaucher’s disease. A recent
synthesis of the stored lipid is normal. (3) The enzy- promising approach is substrate reduction therapy to
matic defect is in the lysosomal degradation pathway inhibit the synthesis of sphingolipids, and gene therapy
of sphingolipids. (4) The extent to which the activity of for lysosomal disorders is currently under investigation.
the affected enzyme is decreased is similar in all tissues. Some examples of the more important lipid storage dis-
There is no effective treatment for many of the diseases, eases are shown in Table 24–1.
though some success has been achieved with enzymes
that have been chemically modified to ensure binding Multiple sulfatase deficiency results in accumula-
to receptors of target cells, eg, to macrophages in the tion of sulfogalactosylceramide, steroid sulfates, and
liver in order to deliver β-glucosidase (glucocerebrosi- proteoglycans owing to a combined deficiency of aryl-
sulfatases A, B, and C and steroid sulfatase.

Table 24–1. Examples of sphingolipidoses.

Disease Enzyme Deficiency Lipid Accumulating1 Clinical Symptoms

Tay-Sachs disease Hexosaminidase A Cer—Glc—Gal(NeuAc)—:: GalNAc Mental retardation, blindness, muscular weakness.
Fabry’s disease α-Galactosidase GM2 Ganglioside

Cer—Glc—Gal—:: Gal Skin rash, kidney failure (full symptoms only in
Globotriaosylceramide males; X-linked recessive).

Metachromatic Arylsulfatase A Cer—Gal—:: OSO3 Mental retardation and psychologic disturbances in
leukodystrophy
3-Sulfogalactosylceramide adults; demyelination.

Krabbe’s disease β-Galactosidase Cer—:: Gal Mental retardation; myelin almost absent.
Galactosylceramide

Gaucher’s disease β-Glucosidase Cer—:: Glc Enlarged liver and spleen, erosion of long bones,
Glucosylceramide mental retardation in infants.

Niemann-Pick Sphingomyelinase Cer—:: P—choline Enlarged liver and spleen, mental retardation; fatal in
disease Sphingomyelin early life.

Farber’s disease Ceramidase Acyl—:: Sphingosine Hoarseness, dermatitis, skeletal deformation, mental
Ceramide retardation; fatal in early life.

1NeuAc, N-acetylneuraminic acid; Cer, ceramide; Glc, glucose; Gal, galactose. —:: , site of deficient enzyme reaction.

204 / CHAPTER 24 (demyelination), and sphingolipidoses (inability to
break down sphingolipids in lysosomes due to inher-
SUMMARY ited defects in hydrolase enzymes).

• Triacylglycerols are the major energy-storing lipids, REFERENCES
whereas phosphoglycerols, sphingomyelin, and gly-
cosphingolipids are amphipathic and have structural Griese M: Pulmonary surfactant in health and human lung dis-
functions in cell membranes as well as other special- eases: state of the art. Eur Respir J 1999;13:1455.
ized roles.
Merrill AH, Sweeley CC: Sphingolipids: metabolism and cell sig-
• Triacylglycerols and some phosphoglycerols are syn- naling. In: Biochemistry of Lipids, Lipoproteins and Mem-
thesized by progressive acylation of glycerol 3-phos- branes. Vance DE, Vance JE (editors). Elsevier, 1996.
phate. The pathway bifurcates at phosphatidate,
forming inositol phospholipids and cardiolipin on Prescott SM et al: Platelet-activating factor and related lipid media-
the one hand and triacylglycerol and choline and tors. Annu Rev Biochem 2000;69:419.
ethanolamine phospholipids on the other.
Ruvolo PP: Ceramide regulates cellular homeostasis via diverse
• Plasmalogens and platelet-activating factor (PAF) are stress signaling pathways. Leukemia 2001;15:1153.
ether phospholipids formed from dihydroxyacetone
phosphate. Schuette CG et al: The glycosphingolipidoses—from disease to
basic principles of metabolism. Biol Chem 1999;380:759.
• Sphingolipids are formed from ceramide (N-acyl-
sphingosine). Sphingomyelin is present in mem- Scriver CR et al (editors): The Metabolic and Molecular Bases of In-
branes of organelles involved in secretory processes herited Disease, 8th ed. McGraw-Hill, 2001.
(eg, Golgi apparatus). The simplest glycosphin-
golipids are a combination of ceramide plus a sugar Tijburg LBM, Geelen MJH, van Golde LMG: Regulation of the
residue (eg, GalCer in myelin). Gangliosides are biosynthesis of triacylglycerol, phosphatidylcholine and phos-
more complex glycosphingolipids containing more phatidylethanolamine in the liver. Biochim Biophys Acta
sugar residues plus sialic acid. They are present in the 1989;1004:1.
outer layer of the plasma membrane, where they con-
tribute to the glycocalyx and are important as anti- Vance DE: Glycerolipid biosynthesis in eukaryotes. In: Biochem-
gens and cell receptors. istry of Lipids, Lipoproteins and Membranes. Vance DE, Vance
JE (editors). Elsevier, 1996.
• Phospholipids and sphingolipids are involved in sev-
eral disease processes, including respiratory distress van Echten G, Sandhoff K: Ganglioside metabolism. Enzymology,
syndrome (lack of lung surfactant), multiple sclerosis topology, and regulation. J Biol Chem 1993;268:5341.

Waite M: Phospholipases. In: Biochemistry of Lipids, Lipoproteins
and Membranes. Vance DE, Vance JE (editors). Elsevier,
1996.

Lipid Transport & Storage 25

Peter A. Mayes, PhD, DSc, & Kathleen M. Botham, PhD, DSc

BIOMEDICAL IMPORTANCE Four Major Groups of Plasma Lipoproteins
Have Been Identified
Fat absorbed from the diet and lipids synthesized by the
liver and adipose tissue must be transported between Because fat is less dense than water, the density of a
the various tissues and organs for utilization and stor- lipoprotein decreases as the proportion of lipid to pro-
age. Since lipids are insoluble in water, the problem of tein increases (Table 25–1). In addition to FFA, four
how to transport them in the aqueous blood plasma is major groups of lipoproteins have been identified that
solved by associating nonpolar lipids (triacylglycerol are important physiologically and in clinical diagnosis.
and cholesteryl esters) with amphipathic lipids (phos- These are (1) chylomicrons, derived from intestinal
pholipids and cholesterol) and proteins to make water- absorption of triacylglycerol and other lipids; (2) very
miscible lipoproteins. low density lipoproteins (VLDL, or pre-β-lipopro-
teins), derived from the liver for the export of triacyl-
In a meal-eating omnivore such as the human, ex- glycerol; (3) low-density lipoproteins (LDL, or β-
cess calories are ingested in the anabolic phase of the lipoproteins), representing a final stage in the catabolism
feeding cycle, followed by a period of negative caloric of VLDL; and (4) high-density lipoproteins (HDL, or
balance when the organism draws upon its carbohy- α-lipoproteins), involved in VLDL and chylomicron
drate and fat stores. Lipoproteins mediate this cycle by metabolism and also in cholesterol transport. Triacyl-
transporting lipids from the intestines as chylomi- glycerol is the predominant lipid in chylomicrons and
crons—and from the liver as very low density lipopro- VLDL, whereas cholesterol and phospholipid are the
teins (VLDL)—to most tissues for oxidation and to predominant lipids in LDL and HDL, respectively
adipose tissue for storage. Lipid is mobilized from adi- (Table 25–1). Lipoproteins may be separated according
pose tissue as free fatty acids (FFA) attached to serum to their electrophoretic properties into ␣-, ␤-, and pre-
albumin. Abnormalities of lipoprotein metabolism ␤-lipoproteins.
cause various hypo- or hyperlipoproteinemias. The
most common of these is diabetes mellitus, where in- Lipoproteins Consist of a Nonpolar
sulin deficiency causes excessive mobilization of FFA Core & a Single Surface Layer of
and underutilization of chylomicrons and VLDL, lead- Amphipathic Lipids
ing to hypertriacylglycerolemia. Most other patho-
logic conditions affecting lipid transport are due pri- The nonpolar lipid core consists of mainly triacylglyc-
marily to inherited defects, some of which cause erol and cholesteryl ester and is surrounded by a sin-
hypercholesterolemia, and premature atherosclerosis. gle surface layer of amphipathic phospholipid and
Obesity—particularly abdominal obesity—is a risk fac- cholesterol molecules (Figure 25–1). These are oriented
tor for increased mortality, hypertension, type 2 dia- so that their polar groups face outward to the aqueous
betes mellitus, hyperlipidemia, hyperglycemia, and vari- medium, as in the cell membrane (Chapter 14). The
ous endocrine dysfunctions. protein moiety of a lipoprotein is known as an apo-
lipoprotein or apoprotein, constituting nearly 70% of
LIPIDS ARE TRANSPORTED IN THE some HDL and as little as 1% of chylomicrons. Some
apolipoproteins are integral and cannot be removed,
PLASMA AS LIPOPROTEINS whereas others are free to transfer to other lipoproteins.

Four Major Lipid Classes Are Present
in Lipoproteins

Plasma lipids consist of triacylglycerols (16%), phos- The Distribution of Apolipoproteins
pholipids (30%), cholesterol (14%), and cholesteryl Characterizes the Lipoprotein
esters (36%) and a much smaller fraction of unesteri-
fied long-chain fatty acids (free fatty acids) (4%). This One or more apolipoproteins (proteins or polypeptides)
latter fraction, the free fatty acids (FFA), is metaboli- are present in each lipoprotein. The major apolipopro-
cally the most active of the plasma lipids. teins of HDL (α-lipoprotein) are designated A (Table

205

206 / CHAPTER 25

Table 25–1. Composition of the lipoproteins in plasma of humans.

Composition

Lipoprotein Source Diameter Density Protein Lipid Main Lipid Apolipoproteins
(nm) (g/mL) (%) (%) Components

Chylomicrons Intestine 90–1000 < 0.95 1–2 98–99 Triacylglycerol A-I, A-II, A-IV,1 B-48, C-I, C-II, C-III,
E

Chylomicron Chylomicrons 45–150 < 1.006 6–8 92–94 Triacylglycerol, B-48, E
remnants phospholipids,
cholesterol

VLDL Liver (intestine) 30–90 0.95–1.006 7–10 90–93 Triacylglycerol B-100, C-I, C-II, C-III

IDL VLDL 25–35 1.006–1.019 11 89 Triacylglycerol, B-100, E
cholesterol

LDL VLDL 20–25 1.019–1.063 21 79 Cholesterol B-100

HDL Liver, intestine, 20–25 1.019–1.063 32 Phospholipids, A-I, A-II, A-IV, C-I, C-II, C-III, D,2 E
HDL1 VLDL, chylo- 10–20 1.063–1.125 33 68 cholesterol
microns
HDL2 67

HDL3 5–10 1.125–1.210 57 43

Preβ-HDL3 < 5 > 1.210 A-I

Albumin/free Adipose > 1.281 99 1 Free fatty acids
fatty acids tissue

Abbreviations: HDL, high-density lipoproteins; IDL, intermediate-density lipoproteins; LDL, low-density lipoproteins; VLDL, very low

density lipoproteins.
1Secreted with chylomicrons but transfers to HDL.
2Associated with HDL2 and HDL3 subfractions.
3Part of a minor fraction known as very high density lipoproteins (VHDL).

25–1). The main apolipoprotein of LDL (β-lipopro- tein receptors in tissues, eg, apo B-100 and apo E for
tein) is apolipoprotein B (B-100) and is found also in the LDL receptor, apo E for the LDL receptor-related
VLDL. Chylomicrons contain a truncated form of apo protein (LRP), which has been identified as the rem-
B (B-48) that is synthesized in the intestine, while nant receptor, and apo A-I for the HDL receptor. The
B-100 is synthesized in the liver. Apo B-100 is one of functions of apo A-IV and apo D, however, are not yet
the longest single polypeptide chains known, having clearly defined.
4536 amino acids and a molecular mass of 550,000 Da.
Apo B-48 (48% of B-100) is formed from the same FREE FATTY ACIDS ARE
mRNA as apo B-100 after the introduction of a stop sig- RAPIDLY METABOLIZED
nal by an RNA editing enzyme. Apo C-I, C-II, and
C-III are smaller polypeptides (molecular mass 7000– The free fatty acids (FFA, nonesterified fatty acids, un-
9000 Da) freely transferable between several different esterified fatty acids) arise in the plasma from lipolysis
lipoproteins. Apo E is found in VLDL, HDL, chylomi- of triacylglycerol in adipose tissue or as a result of the
crons, and chylomicron remnants; it accounts for 5– action of lipoprotein lipase during uptake of plasma tri-
10% of total VLDL apolipoproteins in normal subjects. acylglycerols into tissues. They are found in combina-
tion with albumin, a very effective solubilizer, in con-
Apolipoproteins carry out several roles: (1) they can centrations varying between 0.1 and 2.0 µeq/mL of
form part of the structure of the lipoprotein, eg, apo B; plasma. Levels are low in the fully fed condition and
(2) they are enzyme cofactors, eg, C-II for lipoprotein rise to 0.7–0.8 µeq/mL in the starved state. In uncon-
lipase, A-I for lecithin:cholesterol acyltransferase, or en- trolled diabetes mellitus, the level may rise to as much
zyme inhibitors, eg, apo A-II and apo C-III for lipopro- as 2 µeq/mL.
tein lipase, apo C-I for cholesteryl ester transfer protein;
and (3) they act as ligands for interaction with lipopro-

LIPID TRANSPORT & STORAGE / 207

Peripheral apoprotein are also to be found in chyle; however, most of the
(eg, apo C) plasma VLDL are of hepatic origin. They are the vehi-
cles of transport of triacylglycerol from the liver to
Free Phospholipid the extrahepatic tissues.
cholesterol
Cholesteryl There are striking similarities in the mechanisms of
ester formation of chylomicrons by intestinal cells and of
VLDL by hepatic parenchymal cells (Figure 25–2), per-
Triacylglycerol haps because—apart from the mammary gland—the
intestine and liver are the only tissues from which par-
Core of mainly ticulate lipid is secreted. Newly secreted or “nascent”
nonpolar lipids chylomicrons and VLDL contain only a small amount
of apolipoproteins C and E, and the full complement is
Integral Monolayer of mainly acquired from HDL in the circulation (Figures 25–3
apoprotein amphipathic lipids and 25–4). Apo B is essential for chylomicron and
(eg, apo B) VLDL formation. In abetalipoproteinemia (a rare dis-
ease), lipoproteins containing apo B are not formed and
Figure 25–1. Generalized structure of a plasma lipid droplets accumulate in the intestine and liver.
lipoprotein. The similarities with the structure of the
plasma membrane are to be noted. Small amounts of A more detailed account of the factors controlling
cholesteryl ester and triacylglycerol are to be found in hepatic VLDL secretion is given below.
the surface layer and a little free cholesterol in the core.
CHYLOMICRONS & VERY LOW
Free fatty acids are removed from the blood ex-
tremely rapidly and oxidized (fulfilling 25–50% of en- DENSITY LIPOPROTEINS ARE
ergy requirements in starvation) or esterified to form
triacylglycerol in the tissues. In starvation, esterified RAPIDLY CATABOLIZED
lipids from the circulation or in the tissues are oxidized
as well, particularly in heart and skeletal muscle cells, The clearance of labeled chylomicrons from the blood
where considerable stores of lipid are to be found. is rapid, the half-time of disappearance being under 1
hour in humans. Larger particles are catabolized more
The free fatty acid uptake by tissues is related di- quickly than smaller ones. Fatty acids originating from
rectly to the plasma free fatty acid concentration, which chylomicron triacylglycerol are delivered mainly to adi-
in turn is determined by the rate of lipolysis in adipose pose tissue, heart, and muscle (80%), while about 20%
tissue. After dissociation of the fatty acid-albumin com- goes to the liver. However, the liver does not metabo-
plex at the plasma membrane, fatty acids bind to a lize native chylomicrons or VLDL significantly; thus,
membrane fatty acid transport protein that acts as a the fatty acids in the liver must be secondary to their
transmembrane cotransporter with Na+. On entering metabolism in extrahepatic tissues.
the cytosol, free fatty acids are bound by intracellular
fatty acid-binding proteins. The role of these proteins Triacylglycerols of Chylomicrons & VLDL
in intracellular transport is thought to be similar to that Are Hydrolyzed by Lipoprotein Lipase
of serum albumin in extracellular transport of long-
chain fatty acids. Lipoprotein lipase is located on the walls of blood cap-
illaries, anchored to the endothelium by negatively
TRIACYLGLYCEROL IS TRANSPORTED charged proteoglycan chains of heparan sulfate. It has
been found in heart, adipose tissue, spleen, lung, renal
FROM THE INTESTINES IN medulla, aorta, diaphragm, and lactating mammary
gland, though it is not active in adult liver. It is not
CHYLOMICRONS & FROM THE LIVER IN normally found in blood; however, following injection
of heparin, lipoprotein lipase is released from its hep-
VERY LOW DENSITY LIPOPROTEINS aran sulfate binding into the circulation. Hepatic li-
pase is bound to the sinusoidal surface of liver cells and
By definition, chylomicrons are found in chyle formed is released by heparin. This enzyme, however, does not
only by the lymphatic system draining the intestine. react readily with chylomicrons or VLDL but is con-
They are responsible for the transport of all dietary cerned with chylomicron remnant and HDL metabo-
lipids into the circulation. Small quantities of VLDL lism.

Both phospholipids and apo C-II are required as
cofactors for lipoprotein lipase activity, while apo A-II

208 / CHAPTER 25

A Intestinal lumen B

• RER ••••••
•• •
•••• •
• • • ••••• •••••• ••••
••••••• • • •••••••••••••••••••••••
•
•••••••
•• ••
•

• ••
••••

•••• •••
• •••••
•••••• • •• •• •
• ••••• • •••
•
••
••••
•
••
• ••••
•••••• •• •

G • ••••
•••• RER
SER • •••••••• • •• ••
•• • ••• SER

•

•

•• N

•••••••

N G Bile
C VLDL canaliculus

Fenestra

SD Endothelial
cell
E
Blood Lymph vessel leading Lumen of blood sinusoid
capillary to thoracic duct

Figure 25–2. The formation and secretion of (A) chylomicrons by an intestinal cell and (B) very low density
lipoproteins by a hepatic cell. (RER, rough endoplasmic reticulum; SER, smooth endoplasmic reticulum; G, Golgi
apparatus; N, nucleus; C, chylomicrons; VLDL, very low density lipoproteins; E, endothelium; SD, space of Disse,
containing blood plasma.) Apolipoprotein B, synthesized in the RER, is incorporated into lipoproteins in the SER,
the main site of synthesis of triacylglycerol. After addition of carbohydrate residues in G, they are released from
the cell by reverse pinocytosis. Chylomicrons pass into the lymphatic system. VLDL are secreted into the space
of Disse and then into the hepatic sinusoids through fenestrae in the endothelial lining.

and apo C-III act as inhibitors. Hydrolysis takes place The Action of Lipoprotein Lipase Forms
while the lipoproteins are attached to the enzyme on Remnant Lipoproteins
the endothelium. Triacylglycerol is hydrolyzed progres-
sively through a diacylglycerol to a monoacylglycerol Reaction with lipoprotein lipase results in the loss of
that is finally hydrolyzed to free fatty acid plus glycerol. approximately 90% of the triacylglycerol of chylomi-
Some of the released free fatty acids return to the circu- crons and in the loss of apo C (which returns to HDL)
lation, attached to albumin, but the bulk is transported but not apo E, which is retained. The resulting chy-
into the tissue (Figures 25–3 and 25–4). Heart lipopro- lomicron remnant is about half the diameter of the
tein lipase has a low Km for triacylglycerol, about one- parent chylomicron and is relatively enriched in choles-
tenth of that for the enzyme in adipose tissue. This en- terol and cholesteryl esters because of the loss of triacyl-
ables the delivery of fatty acids from triacylglycerol to glycerol (Figure 25–3). Similar changes occur to
be redirected from adipose tissue to the heart in the VLDL, with the formation of VLDL remnants or IDL
starved state when the plasma triacylglycerol decreases. (intermediate-density lipoprotein) (Figure 25–4).
A similar redirection to the mammary gland occurs
during lactation, allowing uptake of lipoprotein triacyl- The Liver Is Responsible for the Uptake
glycerol fatty acid for milk fat synthesis. The VLDL re- of Remnant Lipoproteins
ceptor plays an important part in the delivery of fatty
acids from VLDL triacylglycerol to adipocytes by bind- Chylomicron remnants are taken up by the liver by re-
ing VLDL and bringing it into close contact with ceptor-mediated endocytosis, and the cholesteryl esters
lipoprotein lipase. In adipose tissue, insulin enhances and triacylglycerols are hydrolyzed and metabolized.
lipoprotein lipase synthesis in adipocytes and its Uptake is mediated by a receptor specific for apo E
translocation to the luminal surface of the capillary en- (Figure 25–3), and both the LDL (apo B-100, E) re-
dothelium. ceptor and the LRP (LDL receptor-related protein)

LIPID TRANSPORT & STORAGE / 209

Dietary TG

Nascent
chylomicron

B-48

SMALL Lymphatics TG
INTESTINE C
Chylomicron
E
A po C, Apo E B-48
A
A TG EXTRAHEPATIC
C TISSUES
E
LDL
(apo B-100, E) PC C C
A
receptor

Cholesterol HDL Apo A, Apo C LIPOPROTEIN LIPASE
Fatty acids

B-48

HL TG
CE
LIVER Fatty acids
Chylomicron
remnant Glycerol

LRP receptor

Figure 25–3. Metabolic fate of chylomicrons. (A, apolipoprotein A; B-48, apolipoprotein B-48; ᭺C ,

apolipoprotein C; E, apolipoprotein E; HDL, high-density lipoprotein; TG, triacylglycerol; C, cholesterol and
cholesteryl ester; P, phospholipid; HL, hepatic lipase; LRP, LDL receptor-related protein.) Only the predominant
lipids are shown.

are believed to take part. Hepatic lipase has a dual role: graded in extrahepatic tissues and 70% in the liver. A
(1) in acting as a ligand to the lipoprotein and (2) in positive correlation exists between the incidence of
hydrolyzing its triacylglycerol and phospholipid. coronary atherosclerosis and the plasma concentra-
tion of LDL cholesterol. For further discussion of the
VLDL is the precursor of IDL, which is then con- regulation of the LDL receptor, see Chapter 26.
verted to LDL. Only one molecule of apo B-100 is
present in each of these lipoprotein particles, and this is HDL TAKES PART IN BOTH
conserved during the transformations. Thus, each LDL
particle is derived from only one VLDL particle (Figure LIPOPROTEIN TRIACYLGLYCEROL
25–4). Two possible fates await IDL. It can be taken up
by the liver directly via the LDL (apo B-100, E) recep- & CHOLESTEROL METABOLISM
tor, or it is converted to LDL. In humans, a relatively
large proportion forms LDL, accounting for the in- HDL is synthesized and secreted from both liver and
creased concentrations of LDL in humans compared intestine (Figure 25–5). However, apo C and apo E are
with many other mammals. synthesized in the liver and transferred from liver HDL
to intestinal HDL when the latter enters the plasma. A
LDL IS METABOLIZED VIA major function of HDL is to act as a repository for the
apo C and apo E required in the metabolism of chy-
THE LDL RECEPTOR lomicrons and VLDL. Nascent HDL consists of discoid
phospholipid bilayers containing apo A and free choles-
The liver and many extrahepatic tissues express the terol. These lipoproteins are similar to the particles
LDL (B-100, E) receptor. It is so designated because it found in the plasma of patients with a deficiency of the
is specific for apo B-100 but not B-48, which lacks the plasma enzyme lecithin:cholesterol acyltransferase
carboxyl terminal domain of B-100 containing the (LCAT) and in the plasma of patients with obstructive
LDL receptor ligand, and it also takes up lipoproteins jaundice. LCAT—and the LCAT activator apo A-I—
rich in apo E. This receptor is defective in familial hy- bind to the disk, and the surface phospholipid and free
percholesterolemia. Approximately 30% of LDL is de- cholesterol are converted into cholesteryl esters and

210 / CHAPTER 25

Nascent
VLDL

B-100

TG o C, Apo E VLDL
C B-100

E Ap EXTRAHEPATIC
C TISSUES

LDL A E TG
(apo B-100, E) E PC C C

receptor C

Fatty acids HDL Apo C LIPOPROTEIN LIPASE
Fatty acids
Cholesterol ? B-100 B-100
C
LIVER TG
LDL CE
IDL
(VLDL remnant)

LDL Glycerol
(apo B-100, E)
Final destruction in
liver, extrahepatic receptor
tissues (eg, lympho-
cytes, fibroblasts) EXTRAHEPATIC
via endocytosis TISSUES

Figure 25–4. Metabolic fate of very low density lipoproteins (VLDL) and production of low-density
lipoproteins (LDL). (A, apolipoprotein A; B-100, apolipoprotein B-100; ᭺C , apolipoprotein C; E, apolipoprotein
E; HDL, high-density lipoprotein; TG, triacylglycerol; IDL, intermediate-density lipoprotein; C, cholesterol and

cholesteryl ester; P, phospholipid.) Only the predominant lipids are shown. It is possible that some IDL is also

metabolized via the LRP.

lysolecithin (Chapter 24). The nonpolar cholesteryl es- then esterified by LCAT, increasing the size of the par-
ters move into the hydrophobic interior of the bilayer, ticles to form the less dense HDL2. The cycle is com-
whereas lysolecithin is transferred to plasma albumin. pleted by the re-formation of HDL3, either after selec-
Thus, a nonpolar core is generated, forming a spherical, tive delivery of cholesteryl ester to the liver via the
pseudomicellar HDL covered by a surface film of polar SR-B1 or by hydrolysis of HDL2 phospholipid and tri-
lipids and apolipoproteins. In this way, the LCAT sys- acylglycerol by hepatic lipase. In addition, free apo A-I
tem is involved in the removal of excess unesterified is released by these processes and forms pre␤-HDL
cholesterol from lipoproteins and tissues. The class B after associating with a minimum amount of phospho-
scavenger receptor B1 (SR-B1) has recently been lipid and cholesterol. Preβ-HDL is the most potent
identified as an HDL receptor in the liver and in form of HDL in inducing cholesterol efflux from the
steroidogenic tissues. HDL binds to the receptor via tissues to form discoidal HDL. Surplus apo A-I is de-
apo A-I and cholesteryl ester is selectively delivered to stroyed in the kidney.
the cells, but the particle itself, including apo A-I, is not
taken up. The transport of cholesterol from the tissues HDL concentrations vary reciprocally with plasma
to the liver is known as reverse cholesterol transport triacylglycerol concentrations and directly with the ac-
and is mediated by an HDL cycle (Figure 25–5). The tivity of lipoprotein lipase. This may be due to surplus
smaller HDL3 accepts cholesterol from the tissues via surface constituents, eg, phospholipid and apo A-I
the ATP-binding cassette transporter-1 (ABC-1). being released during hydrolysis of chylomicrons and
ABC-1 is a member of a family of transporter proteins VLDL and contributing toward the formation of preβ-
that couple the hydrolysis of ATP to the binding of a HDL and discoidal HDL. HDL2 concentrations are in-
substrate, enabling it to be transported across the mem- versely related to the incidence of coronary athero-
brane. After being accepted by HDL3, the cholesterol is sclerosis, possibly because they reflect the efficiency of
reverse cholesterol transport. HDLc (HDL1) is found in

LIPID TRANSPORT & STORAGE / 211

LIVER Bile C and PL A-1 SMALL INTESTINE
bile acids
C Synthesis C LCAT Synthesis
C CE PL
Kidney Discoidal
SR-B1 HDL
HEPATIC
LIPASE A-1 Phospholipid
A-1 PL C bilayer
A-1
C Preβ-HDL TISSUES
CE
PL A-1 ABC-1 C
C
HDL2 CE LCAT
PL
HDL3

Figure 25–5. Metabolism of high-density lipoprotein (HDL) in reverse cholesterol transport.
(LCAT, lecithin:cholesterol acyltransferase; C, cholesterol; CE, cholesteryl ester; PL, phospholipid;
A-I, apolipoprotein A-I; SR-B1, scavenger receptor B1; ABC-1, ATP binding cassette transporter 1.)
Preβ-HDL, HDL2, HDL3—see Table 25–1. Surplus surface constituents from the action of lipopro-
tein lipase on chylomicrons and VLDL are another source of preβ-HDL. Hepatic lipase activity is
increased by androgens and decreased by estrogens, which may account for higher concentra-
tions of plasma HDL2 in women.

the blood of diet-induced hypercholesterolemic ani- Hepatic VLDL Secretion Is Related
mals. It is rich in cholesterol, and its sole apolipopro-
tein is apo E. It appears that all plasma lipoproteins are to Dietary & Hormonal Status
interrelated components of one or more metabolic cy-
cles that together are responsible for the complex The cellular events involved in VLDL formation and
process of plasma lipid transport. secretion have been described above. Hepatic triacyl-
glycerol synthesis provides the immediate stimulus for
THE LIVER PLAYS A CENTRAL ROLE IN the formation and secretion of VLDL. The fatty acids
LIPID TRANSPORT & METABOLISM used are derived from two possible sources: (1) synthe-
sis within the liver from acetyl-CoA derived mainly
The liver carries out the following major functions in from carbohydrate (perhaps not so important in hu-
lipid metabolism: (1) It facilitates the digestion and ab- mans) and (2) uptake of free fatty acids from the circu-
sorption of lipids by the production of bile, which con- lation. The first source is predominant in the well-fed
tains cholesterol and bile salts synthesized within the condition, when fatty acid synthesis is high and the
liver de novo or from uptake of lipoprotein cholesterol level of circulating free fatty acids is low. As triacylglyc-
(Chapter 26). (2) The liver has active enzyme systems erol does not normally accumulate in the liver under
for synthesizing and oxidizing fatty acids (Chapters 21 this condition, it must be inferred that it is transported
and 22) and for synthesizing triacylglycerols and phos- from the liver in VLDL as rapidly as it is synthesized
pholipids (Chapter 24). (3) It converts fatty acids to ke- and that the synthesis of apo B-100 is not rate-limiting.
tone bodies (ketogenesis) (Chapter 22). (4) It plays an Free fatty acids from the circulation are the main source
integral part in the synthesis and metabolism of plasma during starvation, the feeding of high-fat diets, or in di-
lipoproteins (this chapter). abetes mellitus, when hepatic lipogenesis is inhibited.
Factors that enhance both the synthesis of triacylglyc-
erol and the secretion of VLDL by the liver include (1)

212 / CHAPTER 25 causing lipid peroxidation. Some protection against this
is provided by the antioxidant action of vitamin E-sup-
the fed state rather than the starved state; (2) the feed- plemented diets. The action of ethionine is thought to
ing of diets high in carbohydrate (particularly if they be due to a reduction in availability of ATP due to its
contain sucrose or fructose), leading to high rates of li- replacing methionine in S-adenosylmethionine, trap-
pogenesis and esterification of fatty acids; (3) high lev- ping available adenine and preventing synthesis of
els of circulating free fatty acids; (4) ingestion of ATP. Orotic acid also causes fatty liver; it is believed to
ethanol; and (5) the presence of high concentrations of interfere with glycosylation of the lipoprotein, thus in-
insulin and low concentrations of glucagon, which en- hibiting release, and may also impair the recruitment of
hance fatty acid synthesis and esterification and inhibit triacylglycerol to the particles. A deficiency of vitamin
their oxidation (Figure 25–6). E enhances the hepatic necrosis of the choline defi-
ciency type of fatty liver. Added vitamin E or a source
CLINICAL ASPECTS of selenium has a protective effect by combating lipid
peroxidation. In addition to protein deficiency, essen-
Imbalance in the Rate of Triacylglycerol tial fatty acid and vitamin deficiencies (eg, linoleic acid,
Formation & Export Causes Fatty Liver pyridoxine, and pantothenic acid) can cause fatty infil-
tration of the liver.
For a variety of reasons, lipid—mainly as triacylglyc-
erol—can accumulate in the liver (Figure 25–6). Exten- Ethanol Also Causes Fatty Liver
sive accumulation is regarded as a pathologic condition.
When accumulation of lipid in the liver becomes Alcoholism leads to fat accumulation in the liver, hy-
chronic, fibrotic changes occur in the cells that progress perlipidemia, and ultimately cirrhosis. The exact
to cirrhosis and impaired liver function. mechanism of action of ethanol in the long term is still
uncertain. Ethanol consumption over a long period
Fatty livers fall into two main categories. The first leads to the accumulation of fatty acids in the liver that
type is associated with raised levels of plasma free are derived from endogenous synthesis rather than from
fatty acids resulting from mobilization of fat from adi- increased mobilization from adipose tissue. There is no
pose tissue or from the hydrolysis of lipoprotein triacyl- impairment of hepatic synthesis of protein after ethanol
glycerol by lipoprotein lipase in extrahepatic tissues. ingestion. Oxidation of ethanol by alcohol dehydrogen-
The production of VLDL does not keep pace with the ase leads to excess production of NADH.
increasing influx and esterification of free fatty acids, al-
lowing triacylglycerol to accumulate, causing a fatty ALCOHOL
liver. This occurs during starvation and the feeding of DEHYDROGENASE
high-fat diets. The ability to secrete VLDL may also be
impaired (eg, in starvation). In uncontrolled diabetes CH3 CH2 OH NAD+ CH3 CHO
mellitus, twin lamb disease, and ketosis in cattle, Ethanol NADH + H+
fatty infiltration is sufficiently severe to cause visible
pallor (fatty appearance) and enlargement of the liver Acetaldehyde
with possible liver dysfunction.
The NADH generated competes with reducing
The second type of fatty liver is usually due to a equivalents from other substrates, including fatty acids,
metabolic block in the production of plasma lipo- for the respiratory chain, inhibiting their oxidation, and
proteins, thus allowing triacylglycerol to accumulate. decreasing activity of the citric acid cycle. The net effect
Theoretically, the lesion may be due to (1) a block in of inhibiting fatty acid oxidation is to cause increased
apolipoprotein synthesis, (2) a block in the synthesis of esterification of fatty acids in triacylglycerol, resulting
the lipoprotein from lipid and apolipoprotein, (3) a in the fatty liver. Oxidation of ethanol leads to the for-
failure in provision of phospholipids that are found in mation of acetaldehyde, which is oxidized by aldehyde
lipoproteins, or (4) a failure in the secretory mechanism dehydrogenase, producing acetate. Other effects of
itself. ethanol may include increased lipogenesis and choles-
terol synthesis from acetyl-CoA, and lipid peroxidation.
One type of fatty liver that has been studied exten- The increased [NADH]/[NAD+] ratio also causes in-
sively in rats is due to a deficiency of choline, which creased [lactate]/[pyruvate], resulting in hyperlactic-
has therefore been called a lipotropic factor. The an- acidemia, which decreases excretion of uric acid, aggra-
tibiotic puromycin, ethionine (α-amino-γ-mercaptobu- vating gout. Some metabolism of ethanol takes place
tyric acid), carbon tetrachloride, chloroform, phospho- via a cytochrome P450-dependent microsomal ethanol
rus, lead, and arsenic all cause fatty liver and a marked oxidizing system (MEOS) involving NADPH and O2.
reduction in concentration of VLDL in rats. Choline This system increases in activity in chronic alcoholism
will not protect the organism against these agents but
appears to aid in recovery. The action of carbon tetra-
chloride probably involves formation of free radicals

LIPID TRANSPORT & STORAGE / 213

VLDL

Nascent Apo C HDL
VLDL Apo E
BLOOD

LIVER Nascent

HEPATOCYTE VLDL –

Golgi complex Glycosyl
residues

Smooth Orotic acid Destruction Carbon tetrachloride Amino
endoplasmic of surplus apo B-100 Puromycin acids
Carbon Ethionine
reticulum tetrachloride

Cholesterol Apo B-100 Protein
Cholesteryl Apo C M synthesis
Apo E
ester

– M Polyribosomes

Membrane Rough – Nascent
synthesis endoplasmic polypeptide

reticulum chains of
apo B-100
Triacylglycerol* Phospholipid Cholesterol feeding
EFA deficiency

– Lipid
EFA
Choline
TRIACYLGLYCEROL deficiency

1,2-Diacylglycerol CDP-choline Phosphocholine Choline
+ –
Insulin Glucagon
Insulin
Ethanol
+
Acyl-CoA + Oxidation

–

Insulin

FFA Lipogenesis from
carbohydrate

Figure 25–6. The synthesis of very low density lipoprotein (VLDL) in the liver and the possible loci of action of
factors causing accumulation of triacylglycerol and a fatty liver. (EFA, essential fatty acids; FFA, free fatty acids;
HDL, high-density lipoproteins; Apo, apolipoprotein; M, microsomal triacylglycerol transfer protein.) The pathways
indicated form a basis for events depicted in Figure 25–2. The main triacylglycerol pool in liver is not on the direct
pathway of VLDL synthesis from acyl-CoA. Thus, FFA, insulin, and glucagon have immediate effects on VLDL secre-
tion as their effects impinge directly on the small triacylglycerol* precursor pool. In the fully fed state, apo B-100 is
synthesized in excess of requirements for VLDL secretion and the surplus is destroyed in the liver. During transla-
tion of apo B-100, microsomal transfer protein-mediated lipid transport enables lipid to become associated with
the nascent polypeptide chain. After release from the ribosomes, these particles fuse with more lipids from the
smooth endoplasmic reticulum, producing nascent VLDL.

214 / CHAPTER 25

and may account for the increased metabolic clearance BLOOD Glucose
in this condition. Ethanol will also inhibit the metabo- Insulin +
lism of some drugs, eg, barbiturates, by competing for
cytochrome P450-dependent enzymes.

MEOS ADIPOSE TISSUE Glucose 6-phosphate

CH3 CH2 OH + NADPH + H+ + O2

Ethanol CH3 CHO + NADP+ + 2H2O Glycolysis
CO2 PPP
Acetaldehyde
Acetyl-CoA
In some Asian populations and Native Americans,
alcohol consumption results in increased adverse reac- NADPH + H+
tions to acetaldehyde owing to a genetic defect of mito-
chondrial aldehyde dehydrogenase. CO2

Acyl-CoA Glycerol
3-phosphate

Esterification

ADIPOSE TISSUE IS THE MAIN STORE ATP TG
CoA
OF TRIACYLGLYCEROL IN THE BODY HORMONE-
ACYL-CoA SENSITIVE
The triacylglycerol stores in adipose tissue are continu- SYNTHETASE
ally undergoing lipolysis (hydrolysis) and reesterifica- LIPASE
tion (Figure 25–7). These two processes are entirely dif-
ferent pathways involving different reactants and Lipolysis
enzymes. This allows the processes of esterification or
lipolysis to be regulated separately by many nutritional, FFA FFA Glycerol
metabolic, and hormonal factors. The resultant of these (pool 2) (pool 1)
two processes determines the magnitude of the free
fatty acid pool in adipose tissue, which in turn deter- LIPOPROTEIN
mines the level of free fatty acids circulating in the LIPASE
plasma. Since the latter has most profound effects upon
the metabolism of other tissues, particularly liver and FFA Glycerol
muscle, the factors operating in adipose tissue that reg-
ulate the outflow of free fatty acids exert an influence
far beyond the tissue itself.

BLOOD TG
(chylomicrons, VLDL)
The Provision of Glycerol 3-Phosphate
FFA Glycerol
Regulates Esterification: Lipolysis Is
Figure 25–7. Metabolism of adipose tissue. Hor-
Controlled by Hormone-Sensitive Lipase mone-sensitive lipase is activated by ACTH, TSH,
glucagon, epinephrine, norepinephrine, and vaso-
(Figure 25–7) pressin and inhibited by insulin, prostaglandin E1, and
nicotinic acid. Details of the formation of glycerol
Triacylglycerol is synthesized from acyl-CoA and glyc- 3-phosphate from intermediates of glycolysis are
erol 3-phosphate (Figure 24–2). Because the enzyme shown in Figure 24–2. (PPP, pentose phosphate path-
glycerol kinase is not expressed in adipose tissue, glyc- way; TG, triacylglycerol; FFA, free fatty acids; VLDL, very
erol cannot be utilized for the provision of glycerol low density lipoprotein.)
3-phosphate, which must be supplied by glucose via
glycolysis.

Triacylglycerol undergoes hydrolysis by a hormone-
sensitive lipase to form free fatty acids and glycerol.
This lipase is distinct from lipoprotein lipase that cat-
alyzes lipoprotein triacylglycerol hydrolysis before its
uptake into extrahepatic tissues (see above). Since glyc-
erol cannot be utilized, it diffuses into the blood,
whence it is utilized by tissues such as those of the liver
and kidney, which possess an active glycerol kinase.

The free fatty acids formed by lipolysis can be recon- LIPID TRANSPORT & STORAGE / 215
verted in the tissue to acyl-CoA by acyl-CoA syn-
thetase and reesterified with glycerol 3-phosphate to regulated in a coordinate manner by phosphorylation-
form triacylglycerol. Thus, there is a continuous cycle dephosphorylation mechanisms.
of lipolysis and reesterification within the tissue.
However, when the rate of reesterification is not suffi- A principal action of insulin in adipose tissue is to
cient to match the rate of lipolysis, free fatty acids accu- inhibit the activity of hormone-sensitive lipase, reduc-
mulate and diffuse into the plasma, where they bind to ing the release not only of free fatty acids but of glycerol
albumin and raise the concentration of plasma free fatty as well. Adipose tissue is much more sensitive to insulin
acids. than are many other tissues, which points to adipose
tissue as a major site of insulin action in vivo.
Increased Glucose Metabolism Reduces
the Output of Free Fatty Acids Several Hormones Promote Lipolysis

When the utilization of glucose by adipose tissue is in- Other hormones accelerate the release of free fatty acids
creased, the free fatty acid outflow decreases. However, from adipose tissue and raise the plasma free fatty acid
the release of glycerol continues, demonstrating that the concentration by increasing the rate of lipolysis of the
effect of glucose is not mediated by reducing the rate of triacylglycerol stores (Figure 25–8). These include epi-
lipolysis. The effect is due to the provision of glycerol nephrine, norepinephrine, glucagon, adrenocorticotro-
3-phosphate, which enhances esterification of free fatty pic hormone (ACTH), α- and β-melanocyte-stimulat-
acids. Glucose can take several pathways in adipose tis- ing hormones (MSH), thyroid-stimulating hormone
sue, including oxidation to CO2 via the citric acid (TSH), growth hormone (GH), and vasopressin. Many
cycle, oxidation in the pentose phosphate pathway, of these activate the hormone-sensitive lipase. For an
conversion to long-chain fatty acids, and formation of optimal effect, most of these lipolytic processes require
acylglycerol via glycerol 3-phosphate (Figure 25–7). the presence of glucocorticoids and thyroid hor-
When glucose utilization is high, a larger proportion of mones. These hormones act in a facilitatory or per-
the uptake is oxidized to CO2 and converted to fatty missive capacity with respect to other lipolytic en-
acids. However, as total glucose utilization decreases, docrine factors.
the greater proportion of the glucose is directed to the
formation of glycerol 3-phosphate for the esterification The hormones that act rapidly in promoting lipoly-
of acyl-CoA, which helps to minimize the efflux of free sis, ie, catecholamines, do so by stimulating the activity
fatty acids. of adenylyl cyclase, the enzyme that converts ATP to
cAMP. The mechanism is analogous to that responsible
HORMONES REGULATE for hormonal stimulation of glycogenolysis (Chap-
ter 18). cAMP, by stimulating cAMP-dependent pro-
FAT MOBILIZATION tein kinase, activates hormone-sensitive lipase. Thus,
processes which destroy or preserve cAMP influence
Insulin Reduces the Output lipolysis. cAMP is degraded to 5′-AMP by the enzyme
of Free Fatty Acids cyclic 3؅,5؅-nucleotide phosphodiesterase. This en-
zyme is inhibited by methylxanthines such as caffeine
The rate of release of free fatty acids from adipose tissue and theophylline. Insulin antagonizes the effect of the
is affected by many hormones that influence either the lipolytic hormones. Lipolysis appears to be more sensi-
rate of esterification or the rate of lipolysis. Insulin in- tive to changes in concentration of insulin than are glu-
hibits the release of free fatty acids from adipose tissue, cose utilization and esterification. The antilipolytic ef-
which is followed by a fall in circulating plasma free fects of insulin, nicotinic acid, and prostaglandin E1 are
fatty acids. It enhances lipogenesis and the synthesis of accounted for by inhibition of the synthesis of cAMP at
acylglycerol and increases the oxidation of glucose to the adenylyl cyclase site, acting through a Gi protein.
CO2 via the pentose phosphate pathway. All of these ef- Insulin also stimulates phosphodiesterase and the lipase
fects are dependent on the presence of glucose and can phosphatase that inactivates hormone-sensitive lipase.
be explained, to a large extent, on the basis of the abil- The effect of growth hormone in promoting lipolysis is
ity of insulin to enhance the uptake of glucose into adi- dependent on synthesis of proteins involved in the for-
pose cells via the GLUT 4 transporter. Insulin also in- mation of cAMP. Glucocorticoids promote lipolysis via
creases the activity of pyruvate dehydrogenase, acetyl- synthesis of new lipase protein by a cAMP-independent
CoA carboxylase, and glycerol phosphate acyltrans- pathway, which may be inhibited by insulin, and also
ferase, reinforcing the effects of increased glucose up- by promoting transcription of genes involved in the
take on the enhancement of fatty acid and acylglycerol cAMP signal cascade. These findings help to explain
synthesis. These three enzymes are now known to be the role of the pituitary gland and the adrenal cortex in
enhancing fat mobilization. The recently discovered
body weight regulatory hormone, leptin, stimulates

216 / CHAPTER 25

Epinephrine, ( )ACTH, Insulin, prostaglandin E1,
norepinephrine TSH, nicotinic acid
glucagon

β-Adrenergic – ATP
blockers FFA

++ + – +
cAMP
Thyroid hormone

GTP ADENYLYL – Hormone-sensitive Insulin
CYCLASE lipase b Pi +
(inactive)

Growth hormone + – ATP Lipase
–– PPi phosphatase
Inhibitors of cAMP-
protein synthesis dependent Mg2+

Adenosine protein
kinase

Methyl- ADP TRIACYL-
xanthines GLYCEROL
(eg, caffeine) – PHOSPHODI- Hormone-sensitive –
ESTERASE
lipase a FFA +
Diacylglycerol
(active)
FFA +
Thyroid hormone ? + pathway + P 2-Monoacylglycerol
Hormone-sensitive
– – FFA + glycerol
Insulin lipase
5′ AMcPAMP-inde–pendent
2-Monoacylglycerol
Insulin

Inhibitors of lipase

Glucocorticoids protein synthesis

Figure 25–8. Control of adipose tissue lipolysis. (TSH, thyroid-stimulating hormone; FFA, free fatty acids.)
Note the cascade sequence of reactions affording amplification at each step. The lipolytic stimulus is “switched
off” by removal of the stimulating hormone; the action of lipase phosphatase; the inhibition of the lipase and
adenylyl cyclase by high concentrations of FFA; the inhibition of adenylyl cyclase by adenosine; and the removal
of cAMP by the action of phosphodiesterase. ACTH, TSH, and glucagon may not activate adenylyl cyclase in vivo,
since the concentration of each hormone required in vitro is much higher than is found in the circulation. Posi-
tive (᭺+ ) and negative (᭺− ) regulatory effects are represented by broken lines and substrate flow by solid lines.

lipolysis and inhibits lipogenesis by influencing the ac- citrate lyase, a key enzyme in lipogenesis, does not ap-
tivity of the enzymes in the pathways for the break- pear to be present, and other lipogenic enzymes—eg,
down and synthesis of fatty acids. glucose-6-phosphate dehydrogenase and the malic en-
zyme—do not undergo adaptive changes. Indeed, it has
The sympathetic nervous system, through liberation been suggested that in humans there is a “carbohydrate
of norepinephrine in adipose tissue, plays a central role excess syndrome” due to a unique limitation in ability
in the mobilization of free fatty acids. Thus, the in- to dispose of excess carbohydrate by lipogenesis. In
creased lipolysis caused by many of the factors de- birds, lipogenesis is confined to the liver, where it is
scribed above can be reduced or abolished by denerva- particularly important in providing lipids for egg for-
tion of adipose tissue or by ganglionic blockade. mation, stimulated by estrogens. Human adipose tissue
is unresponsive to most of the lipolytic hormones apart
A Variety of Mechanisms Have Evolved for from the catecholamines.
Fine Control of Adipose Tissue Metabolism
On consideration of the profound derangement of
Human adipose tissue may not be an important site of metabolism in diabetes mellitus (due in large part to
lipogenesis. There is no significant incorporation of increased release of free fatty acids from the depots) and
glucose or pyruvate into long-chain fatty acids; ATP- the fact that insulin to a large extent corrects the condi-

OUTSIDE INNER INSIDE LIPID TRANSPORT & STORAGE / 217
MITOCHONDRIAL
tion, it must be concluded that insulin plays a promi-
MEMBRANE nent role in the regulation of adipose tissue metabolism.

Norepinephine F0 F1 BROWN ADIPOSE TISSUE
+
PROMOTES THERMOGENESIS
ATP H+
Brown adipose tissue is involved in metabolism particu-
cAMP synthase larly at times when heat generation is necessary. Thus,
+ the tissue is extremely active in some species in arousal
F0 from hibernation, in animals exposed to cold (nonshiv-
ering thermogenesis), and in heat production in the
H+ Heat newborn animal. Though not a prominent tissue in hu-
mans, it is present in normal individuals, where it could
Hormone- Respiratory be responsible for “diet-induced thermogenesis.” It is
sensitive chain noteworthy that brown adipose tissue is reduced or ab-
sent in obese persons. The tissue is characterized by a
lipase well-developed blood supply and a high content of mi-
tochondria and cytochromes but low activity of ATP
+ synthase. Metabolic emphasis is placed on oxidation of
both glucose and fatty acids. Norepinephrine liberated
Triacyl- H+ H+ from sympathetic nerve endings is important in increas-
glycerol ing lipolysis in the tissue and increasing synthesis of
lipoprotein lipase to enhance utilization of triacylglyc-
FFA erol-rich lipoproteins from the circulation. Oxidation
and phosphorylation are not coupled in mitochondria
+ Thermogenin of this tissue, and the phosphorylation that does occur
Acyl-CoA is at the substrate level, eg, at the succinate thiokinase
Reducing step and in glycolysis. Thus, oxidation produces much
+ equivalents heat, and little free energy is trapped in ATP. A ther-
mogenic uncoupling protein, thermogenin, acts as a
– Heat proton conductance pathway dissipating the electro-
chemical potential across the mitochondrial membrane
Purine β-Oxidation (Figure 25–9).
nucleotides
SUMMARY
Carnitine
transporter • Since nonpolar lipids are insoluble in water, for
transport between the tissues in the aqueous blood
Figure 25–9. Thermogenesis in brown adipose tis- plasma they are combined with amphipathic lipids
sue. Activity of the respiratory chain produces heat in and proteins to make water-miscible lipoproteins.
addition to translocating protons (Chapter 12). These
protons dissipate more heat when returned to the • Four major groups of lipoproteins are recognized:
inner mitochondrial compartment via thermogenin in- Chylomicrons transport lipids resulting from diges-
stead of generating ATP when returning via the F1 ATP tion and absorption. Very low density lipoproteins
synthase. The passage of H+ via thermogenin is inhib- (VLDL) transport triacylglycerol from the liver. Low-
ited by purine nucleotides when brown adipose tissue density lipoproteins (LDL) deliver cholesterol to the
is unstimulated. Under the influence of norepinephrine, tissues, and high-density lipoproteins (HDL) remove
the inhibition is removed by the production of free cholesterol from the tissues in the process known as
fatty acids (FFA) and acyl-CoA. Note the dual role of reverse cholesterol transport.
acyl-CoA in both facilitating the action of thermogenin
and supplying reducing equivalents for the respiratory • Chylomicrons and VLDL are metabolized by hydrol-
chain. + and − signify positive or negative regulatory ysis of their triacylglycerol, and lipoprotein remnants
effects. are left in the circulation. These are taken up by liver,
but some of the remnants (IDL) resulting from
VLDL form LDL which is taken up by the liver and
other tissues via the LDL receptor.

218 / CHAPTER 25 REFERENCES

• Apolipoproteins constitute the protein moiety of Chappell DA, Medh JD: Receptor-mediated mechanisms of
lipoproteins. They act as enzyme activators (eg, apo lipoprotein remnant catabolism. Prog Lipid Res 1998;37:
C-II and apo A-I) or as ligands for cell receptors (eg, 393.
apo A-I, apo E, and apo B-100).
Eaton S et al: Multiple biochemical effects in the pathogenesis of
• Triacylglycerol is the main storage lipid in adipose fatty liver. Eur J Clin Invest 1997;27:719.
tissue. Upon mobilization, free fatty acids and glyc-
erol are released. Free fatty acids are an important Goldberg IJ, Merkel M: Lipoprotein lipase: physiology, biochem-
fuel source. istry and molecular biology. Front Biosci 2001;6:D388.

• Brown adipose tissue is the site of “nonshivering Holm C et al: Molecular mechanisms regulating hormone sensitive
thermogenesis.” It is found in hibernating and new- lipase and lipolysis. Annu Rev Nutr 2000;20:365.
born animals and is present in small quantity in hu-
mans. Thermogenesis results from the presence of an Kaikans RM, Bass NM, Ockner RK: Functions of fatty acid bind-
uncoupling protein, thermogenin, in the inner mito- ing proteins. Experientia 1990;46:617.
chondrial membrane.
Lardy H, Shrago E: Biochemical aspects of obesity. Annu Rev
Biochem 1990;59:689.

Rye K-A et al: Overview of plasma lipid transport. In: Plasma
Lipids and Their Role in Disease. Barter PJ, Rye K-A (editors).
Harwood Academic Publishers, 1999.

Shelness GS, Sellers JA: Very-low-density lipoprotein assembly and
secretion. Curr Opin Lipidol 2001;12:151.

Various authors: Biochemistry of Lipids, Lipoproteins and Mem-
branes. Vance DE, Vance JE (editors). Elsevier, 1996.

Various authors: Brown adipose tissue—role in nutritional energet-
ics. (Symposium.) Proc Nutr Soc 1989;48:165.

Cholesterol Synthesis,Transport, 26
& Excretion

Peter A. Mayes, PhD, DSc, & Kathleen M. Botham, PhD, DSc

BIOMEDICAL IMPORTANCE from mevalonate by loss of CO2 (Figure 26–2). (3) Six
isoprenoid units condense to form squalene. (4) Squa-
Cholesterol is present in tissues and in plasma either as lene cyclizes to give rise to the parent steroid, lanos-
free cholesterol or as a storage form, combined with a terol. (5) Cholesterol is formed from lanosterol (Figure
long-chain fatty acid as cholesteryl ester. In plasma, 26–3).
both forms are transported in lipoproteins (Chapter
25). Cholesterol is an amphipathic lipid and as such is Step 1—Biosynthesis of Mevalonate: HMG-CoA
an essential structural component of membranes and of (3-hydroxy-3-methylglutaryl-CoA) is formed by the re-
the outer layer of plasma lipoproteins. It is synthesized actions used in mitochondria to synthesize ketone bod-
in many tissues from acetyl-CoA and is the precursor of ies (Figure 22–7). However, since cholesterol synthesis
all other steroids in the body such as corticosteroids, sex is extramitochondrial, the two pathways are distinct.
hormones, bile acids, and vitamin D. As a typical prod- Initially, two molecules of acetyl-CoA condense to
uct of animal metabolism, cholesterol occurs in foods form acetoacetyl-CoA catalyzed by cytosolic thiolase.
of animal origin such as egg yolk, meat, liver, and Acetoacetyl-CoA condenses with a further molecule of
brain. Plasma low-density lipoprotein (LDL) is the ve- acetyl-CoA catalyzed by HMG-CoA synthase to form
hicle of uptake of cholesterol and cholesteryl ester into HMG-CoA, which is reduced to mevalonate by
many tissues. Free cholesterol is removed from tissues NADPH catalyzed by HMG-CoA reductase. This is
by plasma high-density lipoprotein (HDL) and trans- the principal regulatory step in the pathway of choles-
ported to the liver, where it is eliminated from the body terol synthesis and is the site of action of the most effec-
either unchanged or after conversion to bile acids in the tive class of cholesterol-lowering drugs, the HMG-CoA
process known as reverse cholesterol transport. Cho- reductase inhibitors (statins) (Figure 26–1).
lesterol is a major constituent of gallstones. However,
its chief role in pathologic processes is as a factor in the Step 2—Formation of Isoprenoid Units: Meval-
genesis of atherosclerosis of vital arteries, causing cere- onate is phosphorylated sequentially by ATP by three
brovascular, coronary, and peripheral vascular disease. kinases, and after decarboxylation (Figure 26–2) the ac-
tive isoprenoid unit, isopentenyl diphosphate, is
CHOLESTEROL IS DERIVED formed.

ABOUT EQUALLY FROM THE DIET Step 3—Six Isoprenoid Units Form Squalene:
Isopentenyl diphosphate is isomerized by a shift of the
& FROM BIOSYNTHESIS double bond to form dimethylallyl diphosphate, then
condensed with another molecule of isopentenyl
A little more than half the cholesterol of the body arises diphosphate to form the ten-carbon intermediate ger-
by synthesis (about 700 mg/d), and the remainder is anyl diphosphate (Figure 26–2). A further condensa-
provided by the average diet. The liver and intestine ac- tion with isopentenyl diphosphate forms farnesyl
count for approximately 10% each of total synthesis in diphosphate. Two molecules of farnesyl diphosphate
humans. Virtually all tissues containing nucleated cells condense at the diphosphate end to form squalene. Ini-
are capable of cholesterol synthesis, which occurs in the tially, inorganic pyrophosphate is eliminated, forming
endoplasmic reticulum and the cytosol. presqualene diphosphate, which is then reduced by
NADPH with elimination of a further inorganic py-
Acetyl-CoA Is the Source of All Carbon rophosphate molecule.
Atoms in Cholesterol
Step 4—Formation of Lanosterol: Squalene can
The biosynthesis of cholesterol may be divided into five fold into a structure that closely resembles the steroid
steps: (1) Synthesis of mevalonate occurs from acetyl- nucleus (Figure 26–3). Before ring closure occurs, squa-
CoA (Figure 26–1). (2) Isoprenoid units are formed lene is converted to squalene 2,3-epoxide by a mixed-

219

220 / CHAPTER 26

O Farnesyl Diphosphate Gives Rise
to Dolichol & Ubiquinone
CH3 C S CoA
2 Acetyl-CoA The polyisoprenoids dolichol (Figure 14–20 and
Chapter 47) and ubiquinone (Figure 12–5) are formed
THIOLASE from farnesyl diphosphate by the further addition of up
to 16 (dolichol) or 3–7 (ubiquinone) isopentenyl
CoA SH diphosphate residues, respectively. Some GTP-binding
CH3 O proteins in the cell membrane are prenylated with far-
nesyl or geranylgeranyl (20 carbon) residues. Protein
C CH2 C S CoA prenylation is believed to facilitate the anchoring of
O Acetoacetyl-CoA O proteins into lipoid membranes and may also be in-
volved in protein-protein interactions and membrane-
H2O CH3 C S CoA associated protein trafficking.
HMG-CoA SYNTHASE Acetyl-CoA
CHOLESTEROL SYNTHESIS IS
CoA SH
CONTROLLED BY REGULATION
–OOC CH2 CH3 O S CoA
C CH2 C OF HMG-CoA REDUCTASE

OH Regulation of cholesterol synthesis is exerted near the
3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) beginning of the pathway, at the HMG-CoA reductase
step. The reduced synthesis of cholesterol in starving
Bile acid, cholesterol 2NADPH + 2H+ animals is accompanied by a decrease in the activity of
the enzyme. However, it is only hepatic synthesis that is
HMG-CoA REDUCTASE Statins, eg, inhibited by dietary cholesterol. HMG-CoA reductase
simvastatin in liver is inhibited by mevalonate, the immediate prod-
SH uct of the pathway, and by cholesterol, the main prod-
2NADP+ + CoA uct. Cholesterol (or a metabolite, eg, oxygenated sterol)
represses transcription of the HMG-CoA reductase
Mevalonate CH3 gene and is also believed to influence translation. A di-
urnal variation occurs in both cholesterol synthesis
–OOC CH2 C CH2 CH2 OH and reductase activity. In addition to these mechanisms
regulating the rate of protein synthesis, the enzyme ac-
OH tivity is also modulated more rapidly by posttransla-
Mevalonate tional modification (Figure 26–4). Insulin or thyroid
hormone increases HMG-CoA reductase activity,
Figure 26–1. Biosynthesis of mevalonate. HMG-CoA whereas glucagon or glucocorticoids decrease it. Activ-
reductase is inhibited by atorvastatin, pravastatin, and ity is reversibly modified by phosphorylation-dephos-
simvastatin. The open and solid circles indicate the fate phorylation mechanisms, some of which may be
of each of the carbons in the acetyl moiety of acetyl- cAMP-dependent and therefore immediately responsive
CoA. to glucagon. Attempts to lower plasma cholesterol in
humans by reducing the amount of cholesterol in the
function oxidase in the endoplasmic reticulum, squa- diet produce variable results. Generally, a decrease of
lene epoxidase. The methyl group on C14 is transferred 100 mg in dietary cholesterol causes a decrease of ap-
to C13 and that on C8 to C14 as cyclization occurs, cat- proximately 0.13 mmol/L of serum.
alyzed by oxidosqualene:lanosterol cyclase.
MANY FACTORS INFLUENCE THE
Step 5—Formation of Cholesterol: The forma-
tion of cholesterol from lanosterol takes place in the CHOLESTEROL BALANCE IN TISSUES
membranes of the endoplasmic reticulum and involves
changes in the steroid nucleus and side chain (Figure In tissues, cholesterol balance is regulated as follows (Fig-
26–3). The methyl groups on C14 and C4 are removed ure 26–5): Cell cholesterol increase is due to uptake of
to form 14-desmethyl lanosterol and then zymosterol. cholesterol-containing lipoproteins by receptors, eg, the
The double bond at C8–C9 is subsequently moved to LDL receptor or the scavenger receptor; uptake of free
C5–C6 in two steps, forming desmosterol. Finally, the cholesterol from cholesterol-rich lipoproteins to the cell
double bond of the side chain is reduced, producing
cholesterol. The exact order in which the steps de-
scribed actually take place is not known with cer-
tainty.

CH3 OH ATP ADP CH3 OH
C CH2
–OOC Mg2+ –OOC

C CH2

CH2 CH2 OH MEVALONATE CH2 CH2 O P
KINASE

Mevalonate Mevalonate 5-phosphate
ATP

PHOSPHOMEVALONATE Mg2+
KINASE

ADP

CH3 OP ADP ATP CH3 OH
C CH2 C CH2
–OOC Mg2+ –OOC

CH2 CH2 OP P DIPHOSPHOMEVALONATE CH2 CH2 O P P
KINASE

Mevalonate 3-phospho-5-diphosphate Mevalonate 5-diphosphate

CO2 + Pi

HMG-CoA DIPHOSPHO-
MEVALONATE
trans -Methyl- CH3 DECARBOXYLASE CH3
glutaconate C
shunt CH2 C CH2

CH3 CH OP P ISOPENTENYL- CH2 CH2 O P P
DIPHOSPHATE Isopentenyl
3,3-Dimethylallyl diphosphate
diphosphate ISOMERASE

Isopentenyl tRNA CIS-PRENYL PPi
Prenylated proteins TRANSFERASE CH3

CH3

C CH2 C CH2

CH3 CH CH2 CH O P P

Geranyl diphosphate

CIS-PRENYL
TRANSFERASE

TRANS-PRENYL PPi CIS-PRENYL
TRANSFERASE TRANSFERASE
C* H2
Side chain of Dolichol
ubiquinone O PP

Heme a Farnesyl diphosphate

SQUALENE SYNTHETASE NADPH + H+
Mg2+, Mn2+
2PPi
NADP+

C* H2

*CH2

Squalene

Figure 26–2. Biosynthesis of squalene, ubiquinone, dolichol, and other polyisoprene derivatives. (HMG,
3-hydroxy-3-methylglutaryl; ⋅×⋅⋅⋅, cytokinin.) A farnesyl residue is present in heme a of cytochrome oxidase.
The carbon marked with asterisk becomes C11 or C12 in squalene. Squalene synthetase is a microsomal en-
zyme; all other enzymes indicated are soluble cytosolic proteins, and some are found in peroxisomes.

221

222 / CHAPTER 26

O S CoA –OOC CH3 CH2OH CH3 CH3 CH2–
CH3 C CH2 C CH2 C CH

OH CO2 H2O
Mevalonate
Acetyl-CoA Isoprenoid unit

CH3 CH2 CH3 CH2
C CH2 C CH2

Squalene 12 13 CH 24 CH3 12 13 CH 24 CH3
epoxide CH C CH C
CH2 HC * *CH2 HC
CH3 CH3
11 CH2 CH2 11 CH2 CH2

1 CH2 CH3 CH 8 14 C CH2 SQUALENE 1 CH2 CH3 CH 8 14 C CH2
C C CH3
H2C C CC CH3 EPOXIDASE H2C
HC3 CH3 CH CH3
CH3 NADPH 1/2 O2 HC3 X6
O CH CH2 FAD CH2

CH2 C CH2 Squalene

CH3 OXIDOSQUALENE: CH3 CH3
LANOSTEROL
CYCLASE

H COOH 2CO2

4 14 NADPH 14 O2,NNAADD+PH 8
8 O2 HO
HO HO 14-Desmethyl Zymosterol
Lanosterol lanosterol

21 22 ISOMERASE
24
18 20 23 26
7
24 25 NADPH 24
∆7,24-Cholestadienol
19 11 12 13 17 27 NADPH
C 16 O2
14 D 15

19 ∆24-REDUCTASE
2 10 8
AB
35 7 3
4 6
HO HO 5 HO
–
Cholesterol Desmosterol
(24-dehydrocholesterol)

Triparanol

Figure 26–3. Biosynthesis of cholesterol. The numbered positions are those of the steroid nucleus and the
open and solid circles indicate the fate of each of the carbons in the acetyl moiety of acetyl-CoA. Asterisks: Refer
to labeling of squalene in Figure 26–2.

CHOLESTEROL SYNTHESIS, TRANSPORT, & EXCRETION / 223

REDUCTASE

ATP KINASE Pi
(inactive)

REDUCTASE P PROTEIN +
KINASE PHOSPHATASES Insulin
KINASE REDUCTASE
KINASE H2O ?
ADP (active)
–
Glucagon

+

ATP ADP

Inhibitor-1- cAMP
+
phosphate*

HMG-CoA HMG-CoA HMG-CoA
LDL-cholesterol REDUCTASE P REDUCTASE

Cholesterol (active) (inactive)

Oxysterols Pi PROTEIN H2O
– PHOSPHATASES
? Insulin
Enzyme synthesis +

–

Figure 26–4. Possible mechanisms in the regulation of cholesterol synthesis by HMG-CoA reductase. Insulin
has a dominant role compared with glucagon. Asterisk: See Figure 18–6.

membrane; cholesterol synthesis; and hydrolysis of cho- ity; and down-regulates synthesis of the LDL receptor.
lesteryl esters by the enzyme cholesteryl ester hydrolase. Thus, the number of LDL receptors on the cell surface
Decrease is due to efflux of cholesterol from the mem- is regulated by the cholesterol requirement for mem-
brane to HDL, promoted by LCAT (lecithin:cholesterol branes, steroid hormones, or bile acid synthesis (Figure
acyltransferase) (Chapter 25); esterification of cholesterol 26–5). The apo B-100, E receptor is a “high-affinity”
by ACAT (acyl-CoA:cholesterol acyltransferase); and uti- LDL receptor, which may be saturated under most cir-
lization of cholesterol for synthesis of other steroids, such cumstances. Other “low-affinity” LDL receptors also
as hormones, or bile acids in the liver. appear to be present in addition to a scavenger path-
way, which is not regulated.
The LDL Receptor Is Highly Regulated
CHOLESTEROL IS TRANSPORTED
LDL (apo B-100, E) receptors occur on the cell surface BETWEEN TISSUES IN PLASMA
in pits that are coated on the cytosolic side of the cell LIPOPROTEINS
membrane with a protein called clathrin. The glycopro- (Figure 26–6)
tein receptor spans the membrane, the B-100 binding
region being at the exposed amino terminal end. After In Western countries, the total plasma cholesterol in
binding, LDL is taken up intact by endocytosis. The humans is about 5.2 mmol/L, rising with age, though
apoprotein and cholesteryl ester are then hydrolyzed in there are wide variations between individuals. The
the lysosomes, and cholesterol is translocated into the greater part is found in the esterified form. It is trans-
cell. The receptors are recycled to the cell surface. This ported in lipoproteins of the plasma, and the highest
influx of cholesterol inhibits in a coordinated man- proportion of cholesterol is found in the LDL. Dietary
ner HMG-CoA synthase, HMG-CoA reductase, and, cholesterol equilibrates with plasma cholesterol in days
therefore, cholesterol synthesis; stimulates ACAT activ-

224 / CHAPTER 26

CELL MEMBRANE

Recycling Receptor –
vesicle synthesis
LDL (apo B -100, E)
receptors Lysosome Down-regulation Cholesterol
synthesis
(in coated pits) –

CE + ACAT

LDL Endosome C CE
LDL CE HYDROLASE
Unesterified
CE cholesterol

CE pool CE
(mainly in membranes)
Coated
vesicle CE C
Lysosome
Scavenger receptor or
nonregulated pathway

LDL C Synthesis
VLDL of steroids

ABC-1

A-1 CE A-1
PL C LCAT PL

Preβ-HDL HDL3

Figure 26–5. Factors affecting cholesterol balance at the cellular level. Reverse cholesterol transport may
be initiated by preβ HDL binding to the ABC-1 transporter protein via apo A-I. Cholesterol is then moved out
of the cell via the transporter, lipidating the HDL, and the larger particles then dissociate from the ABC-1 mol-
ecule. (C, cholesterol; CE, cholesteryl ester; PL, phospholipid; ACAT, acyl-CoA:cholesterol acyltransferase; LCAT,
lecithin:cholesterol acyltransferase; A-I, apolipoprotein A-I; LDL, low-density lipoprotein; VLDL, very low den-
sity lipoprotein.) LDL and HDL are not shown to scale.

and with tissue cholesterol in weeks. Cholesteryl ester ates a concentration gradient and draws in cholesterol
in the diet is hydrolyzed to cholesterol, which is then from tissues and from other lipoproteins (Figures 26–5
absorbed by the intestine together with dietary unesteri- and 26–6), thus enabling HDL to function in reverse
fied cholesterol and other lipids. With cholesterol syn- cholesterol transport (Figure 25–5).
thesized in the intestines, it is then incorporated into
chylomicrons. Of the cholesterol absorbed, 80–90% is Cholesteryl Ester Transfer Protein
esterified with long-chain fatty acids in the intestinal Facilitates Transfer of Cholesteryl Ester
mucosa. Ninety-five percent of the chylomicron choles- From HDL to Other Lipoproteins
terol is delivered to the liver in chylomicron remnants,
and most of the cholesterol secreted by the liver in This protein is found in plasma of humans and many
VLDL is retained during the formation of IDL and ul- other species, associated with HDL. It facilitates transfer
timately LDL, which is taken up by the LDL receptor of cholesteryl ester from HDL to VLDL, IDL, and LDL
in liver and extrahepatic tissues (Chapter 25). in exchange for triacylglycerol, relieving product inhibi-
tion of LCAT activity in HDL. Thus, in humans, much
Plasma LCAT Is Responsible for Virtually of the cholesteryl ester formed by LCAT finds its way to
All Plasma Cholesteryl Ester in Humans the liver via VLDL remnants (IDL) or LDL (Figure
26–6). The triacylglycerol-enriched HDL2 delivers its
LCAT activity is associated with HDL containing apo cholesterol to the liver in the HDL cycle (Figure 25–5).
A-I. As cholesterol in HDL becomes esterified, it cre-

CHOLESTEROL SYNTHESIS, TRANSPORT, & EXCRETION / 225

ENTEROHEPATIC CIRCULATION Diet (0.4 g/d)
HEPATIC PORTAL VEIN C
GALL CE
BLADDER
Synthesis –
– Bile acids BILE DUCT

Unesterified (total pool, 3–5 g)
cholesterol
ACAT CE CE
pool
C HL VLDL C
C TG
C TG, CE Chylomicron Bile ILEUM
LDL C acids
LIVER CE

LRP receptor CE

TG (apo B-100, E) TG
CE
C receptor CE 8–99
Chylomicron LCAT C
remnant %
LDL 9

CE TG
C TG CE

CE CE C Bile acids
TG C CETP (0.6 g/d) (0.4 g/d)
TG CE
CE A-I Feces
C IDL HDL
(VLDL remnant)

LDL C LPL C
(apo B-100, E) Synthesis
C receptor

EXTRAHEPATIC
TISSUES

CE

Figure 26–6. Transport of cholesterol between the tissues in humans. (C, unesterified cholesterol; CE, cho-
lesteryl ester; TG, triacylglycerol; VLDL, very low density lipoprotein; IDL, intermediate-density lipoprotein; LDL,
low-density lipoprotein; HDL, high-density lipoprotein; ACAT, acyl-CoA:cholesterol acyltransferase; LCAT,
lecithin:cholesterol acyltransferase; A-I, apolipoprotein A-I; CETP, cholesteryl ester transfer protein; LPL, lipopro-
tein lipase; HL, hepatic lipase; LRP, LDL receptor-related protein.)

CHOLESTEROL IS EXCRETED FROM THE feces; it is formed from cholesterol by the bacteria in
BODY IN THE BILE AS CHOLESTEROL OR the lower intestine.
BILE ACIDS (SALTS)
Bile Acids Are Formed From Cholesterol
About 1 g of cholesterol is eliminated from the body
per day. Approximately half is excreted in the feces after The primary bile acids are synthesized in the liver from
conversion to bile acids. The remainder is excreted as cholesterol. These are cholic acid (found in the largest
cholesterol. Coprostanol is the principal sterol in the amount) and chenodeoxycholic acid (Figure 26–7).

226 / CHAPTER 26

12 17 Vitamin C
NADPH + H+ NADP+
3 7 7
O2
HO Cholesterol HO OH
7α-HYDROXYLASE
7α-Hydroxycholesterol

Bile 12α-HYDROX- O2
acids YLASE NADPH + H+
Vitamin C 2 CoA SH
deficiency O2
NADPH + H+ Propionyl-CoA
(Several
2 CoA SH steps)

Propionyl-CoA

OH H C S CoA
O
C N (CH2)2 SO3H
O CoA SH OH HO OH
CoA H
HO OH Taurine 12 C S Chenodeoxycholyl-CoA
H O

Taurocholic acid Glycine OH
(primary bile acid) SH HO H

CoA Cholyl-CoA

OH H Tauro- and glyco-
chenodeoxycholic acid
C N CH2COOH OH
O COOH (primary bile acids)

HO OH * Deconjugation
H + 7α-dehydroxylation

Glycocholic acid COOH
(primary bile acid)
HO
* Deconjugation HO H
H
+ 7α-dehydroxylation Lithocholic acid
Deoxycholic acid (secondary bile acid)

(secondary bile acid)

Figure 26–7. Biosynthesis and degradation of bile acids. A second pathway in mitochondria involves hy-
droxylation of cholesterol by sterol 27-hydroxylase. Asterisk: Catalyzed by microbial enzymes.

The 7α-hydroxylation of cholesterol is the first and chenodeoxycholyl-CoA (Figure 26–7). A second path-
principal regulatory step in the biosynthesis of bile acids way in mitochondria involving the 27-hydroxylation of
catalyzed by 7␣-hydroxylase, a microsomal enzyme. A cholesterol by sterol 27-hydroxylase as the first step is
responsible for a significant proportion of the primary
typical monooxygenase, it requires oxygen, NADPH, bile acids synthesized. The primary bile acids (Figure
26–7) enter the bile as glycine or taurine conjugates.
and cytochrome P450. Subsequent hydroxylation steps Conjugation takes place in peroxisomes. In humans, the
ratio of the glycine to the taurine conjugates is normally
are also catalyzed by monooxygenases. The pathway of 3:1. In the alkaline bile, the bile acids and their conju-

bile acid biosynthesis divides early into one subpathway
leading to cholyl-CoA, characterized by an extra α-OH
group on position 12, and another pathway leading to

CHOLESTEROL SYNTHESIS, TRANSPORT, & EXCRETION / 227

gates are assumed to be in a salt form—hence the term ized by the deposition of cholesterol and cholesteryl
“bile salts.” ester from the plasma lipoproteins into the artery wall.
Diseases in which prolonged elevated levels of VLDL,
A portion of the primary bile acids in the intestine is IDL, chylomicron remnants, or LDL occur in the
subjected to further changes by the activity of the in- blood (eg, diabetes mellitus, lipid nephrosis, hypothy-
testinal bacteria. These include deconjugation and 7α- roidism, and other conditions of hyperlipidemia) are
dehydroxylation, which produce the secondary bile often accompanied by premature or more severe ather-
acids, deoxycholic acid and lithocholic acid. osclerosis. There is also an inverse relationship between
HDL (HDL2) concentrations and coronary heart dis-
Most Bile Acids Return to the Liver ease, and some consider that the most predictive rela-
in the Enterohepatic Circulation tionship is the LDL:HDL cholesterol ratio. This is
consistent with the function of HDL in reverse choles-
Although products of fat digestion, including choles- terol transport. Susceptibility to atherosclerosis varies
terol, are absorbed in the first 100 cm of small intestine, widely among species, and humans are one of the few
the primary and secondary bile acids are absorbed al- in which the disease can be induced by diets high in
most exclusively in the ileum, and 98–99% are re- cholesterol.
turned to the liver via the portal circulation. This is
known as the enterohepatic circulation (Figure 26–6). Diet Can Play an Important Role in
However, lithocholic acid, because of its insolubility, is
not reabsorbed to any significant extent. Only a small Reducing Serum Cholesterol
fraction of the bile salts escapes absorption and is there-
fore eliminated in the feces. Nonetheless, this represents Hereditary factors play the greatest role in determining
a major pathway for the elimination of cholesterol. individual serum cholesterol concentrations; however,
Each day the small pool of bile acids (about 3–5 g) is dietary and environmental factors also play a part, and
cycled through the intestine six to ten times and an the most beneficial of these is the substitution in the
amount of bile acid equivalent to that lost in the feces is diet of polyunsaturated and monounsaturated fatty
synthesized from cholesterol, so that a pool of bile acids acids for saturated fatty acids. Plant oils such as corn oil
of constant size is maintained. This is accomplished by and sunflower seed oil contain a high proportion of
a system of feedback controls. polyunsaturated fatty acids, while olive oil contains a
high concentration of monounsaturated fatty acids. On
Bile Acid Synthesis Is Regulated the other hand, butterfat, beef fat, and palm oil contain
at the 7␣-Hydroxylase Step a high proportion of saturated fatty acids. Sucrose and
fructose have a greater effect in raising blood lipids, par-
The principal rate-limiting step in the biosynthesis of ticularly triacylglycerols, than do other carbohydrates.
bile acids is at the cholesterol 7␣-hydroxylase reac-
tion (Figure 26–7). The activity of the enzyme is feed- The reason for the cholesterol-lowering effect of
back-regulated via the nuclear bile acid-binding recep- polyunsaturated fatty acids is still not fully understood.
tor farnesoid X receptor (FXR). When the size of the It is clear, however, that one of the mechanisms in-
bile acid pool in the enterohepatic circulation increases, volved is the up-regulation of LDL receptors by poly-
FXR is activated and transcription of the cholesterol and monounsaturated as compared with saturated fatty
7α-hydroxylase gene is suppressed. Chenodeoxycholic acids, causing an increase in the catabolic rate of LDL,
acid is particularly important in activating FXR. Cho- the main atherogenic lipoprotein. In addition, saturated
lesterol 7α-hydroxylase activity is also enhanced by fatty acids cause the formation of smaller VLDL parti-
cholesterol of endogenous and dietary origin and regu- cles that contain relatively more cholesterol, and they
lated by insulin, glucagon, glucocorticoids, and thyroid are utilized by extrahepatic tissues at a slower rate than
hormone. are larger particles—tendencies that may be regarded as
atherogenic.

CLINICAL ASPECTS Lifestyle Affects the Serum
Cholesterol Level
The Serum Cholesterol Is Correlated With
the Incidence of Atherosclerosis & Additional factors considered to play a part in coronary
Coronary Heart Disease heart disease include high blood pressure, smoking,
male gender, obesity (particularly abdominal obesity),
While cholesterol is believed to be chiefly concerned in lack of exercise, and drinking soft as opposed to hard
the relationship, other serum lipids such as triacylglyc- water. Factors associated with elevation of plasma FFA
erols may also play a role. Atherosclerosis is character- followed by increased output of triacylglycerol and cho-

228 / CHAPTER 26 of coronary heart disease. This may be due to elevation
of HDL concentrations resulting from increased syn-
lesterol into the circulation in VLDL include emotional thesis of apo A-I and changes in activity of cholesteryl
stress and coffee drinking. Premenopausal women ap- ester transfer protein. It has been claimed that red wine
pear to be protected against many of these deleterious is particularly beneficial, perhaps because of its content
factors, and this is thought to be related to the benefi- of antioxidants. Regular exercise lowers plasma LDL
cial effects of estrogen. There is an association between
moderate alcohol consumption and a lower incidence

Table 26–1. Primary disorders of plasma lipoproteins (dyslipoproteinemias).

Name Defect Remarks

Hypolipoproteinemias No chylomicrons, VLDL, or LDL are Rare; blood acylglycerols low; intestine and liver
Abetalipoproteinemia formed because of defect in the accumulate acylglycerols. Intestinal malabsorp-
loading of apo B with lipid. tion. Early death avoidable by administration of
large doses of fat-soluble vitamins, particularly
vitamin E.

Familial alpha-lipoprotein deficiency All have low or near absence of HDL. Tendency toward hypertriacylglycerolemia as a

Tangier disease result of absence of apo C-II, causing inactive

Fish-eye disease LPL. Low LDL levels. Atherosclerosis in the el-

Apo-A-I deficiencies derly.

Hyperlipoproteinemias Hypertriacylglycerolemia due to de- Slow clearance of chylomicrons and VLDL. Low
Familial lipoprotein lipase ficiency of LPL, abnormal LPL, or apo levels of LDL and HDL. No increased risk of coro-
deficiency (type I) C-II deficiency causing inactive LPL. nary disease.

Familial hypercholesterolemia Defective LDL receptors or mutation Elevated LDL levels and hypercholesterolemia,
(type IIa)
in ligand region of apo B-100. resulting in atherosclerosis and coronary disease.

Familial type III hyperlipoprotein- Deficiency in remnant clearance by Increase in chylomicron and VLDL remnants of
emia (broad beta disease, rem-
nant removal disease, familial the liver is due to abnormality in apo density < 1.019 (β-VLDL). Causes hypercholes-
dysbetalipoproteinemia) terolemia, xanthomas, and atherosclerosis.
E. Patients lack isoforms E3 and E4

and have only E2, which does not
react with the E receptor.1

Familial hypertriacylglycerolemia Overproduction of VLDL often Cholesterol levels rise with the VLDL concentra-
(type IV) associated with glucose intolerance tion. LDL and HDL tend to be subnormal. This
and hyperinsulinemia. type of pattern is commonly associated with
coronary heart disease, type II diabetes mellitus,
obesity, alcoholism, and administration of
progestational hormones.

Familial hyperalphalipoproteinemia Increased concentrations of HDL. A rare condition apparently beneficial to health
and longevity.

Hepatic lipase deficiency Deficiency of the enzyme leads to Patients have xanthomas and coronary heart
accumulation of large triacylgly- disease.
cerol-rich HDL and VLDL remnants.

Familial lecithin:cholesterol Absence of LCAT leads to block in Plasma concentrations of cholesteryl esters and
acyltransferase (LCAT) deficiency reverse cholesterol transport. HDL lysolecithin are low. Present is an abnormal LDL
remains as nascent disks incapable fraction, lipoprotein X, found also in patients
of taking up and esterifying choles- with cholestasis. VLDL is abnormal (β-VLDL).
terol.

Familial lipoprotein(a) excess Lp(a) consists of 1 mol of LDL Premature coronary heart disease due to athero-

attached to 1 mol of apo(a). Apo(a) sclerosis, plus thrombosis due to inhibition of

shows structural homologies to plas- fibrinolysis.

minogen.

1There is an association between patients possessing the apo E4 allele and the incidence of Alzheimer’s disease. Apparently, apo E4 binds
more avidly to β-amyloid found in neuritic plaques.

CHOLESTEROL SYNTHESIS, TRANSPORT, & EXCRETION / 229

but raises HDL. Triacylglycerol concentrations are also acids, and vitamin D. It also plays an important
reduced, due most likely to increased insulin sensitivity, structural role in membranes and in the outer layer of
which enhances expression of lipoprotein lipase. lipoproteins.

When Diet Changes Fail, Hypolipidemic • Cholesterol is synthesized in the body entirely from
Drugs Will Reduce Serum Cholesterol acetyl-CoA. Three molecules of acetyl-CoA form
& Triacylglycerol mevalonate via the important regulatory reaction for
the pathway, catalyzed by HMG-CoA reductase.
Significant reductions of plasma cholesterol can be ef- Next, a five-carbon isoprenoid unit is formed, and
fected medically by the use of cholestyramine resin or six of these condense to form squalene. Squalene un-
surgically by the ileal exclusion operations. Both proce- dergoes cyclization to form the parent steroid lanos-
dures block the reabsorption of bile acids, causing in- terol, which, after the loss of three methyl groups,
creased bile acid synthesis in the liver. This increases forms cholesterol.
cholesterol excretion and up-regulates LDL receptors,
lowering plasma cholesterol. Sitosterol is a hypocholes- • Cholesterol synthesis in the liver is regulated partly
terolemic agent that acts by blocking the absorption of by cholesterol in the diet. In tissues, cholesterol bal-
cholesterol from the gastrointestinal tract. ance is maintained between the factors causing gain
of cholesterol (eg, synthesis, uptake via the LDL or
Several drugs are known to block the formation of scavenger receptors) and the factors causing loss of
cholesterol at various stages in the biosynthetic path- cholesterol (eg, steroid synthesis, cholesteryl ester for-
way. The statins inhibit HMG-CoA reductase, thus mation, excretion). The activity of the LDL receptor
up-regulating LDL receptors. Statins currently in use is modulated by cellular cholesterol levels to achieve
include atorvastatin, simvastatin, and pravastatin. Fi- this balance. In reverse cholesterol transport, HDL
brates such as clofibrate and gemfibrozil act mainly to (preβ-HDL, discoidal, or HDL3) takes up cholesterol
lower plasma triacylglycerols by decreasing the secretion from the tissues and LCAT esterifies it and deposits
of triacylglycerol and cholesterol-containing VLDL by it in the core of HDL, which is converted to HDL2.
the liver. In addition, they stimulate hydrolysis of The cholesteryl ester in HDL2 is taken up by the
VLDL triacylglycerols by lipoprotein lipase. Probucol liver, either directly or after transfer to VLDL, IDL,
appears to increase LDL catabolism via receptor- or LDL via the cholesteryl ester transfer protein.
independent pathways, but its antioxidant properties
may be more important in preventing accumulation of • Excess cholesterol is excreted from the liver in the
oxidized LDL, which has enhanced atherogenic proper- bile as cholesterol or bile salts. A large proportion of
ties, in arterial walls. Nicotinic acid reduces the flux of bile salts is absorbed into the portal circulation and
FFA by inhibiting adipose tissue lipolysis, thereby in- returned to the liver as part of the enterohepatic cir-
hibiting VLDL production by the liver. culation.

Primary Disorders of the Plasma • Elevated levels of cholesterol present in VLDL, IDL,
Lipoproteins (Dyslipoproteinemias) or LDL are associated with atherosclerosis, whereas
Are Inherited high levels of HDL have a protective effect.

Inherited defects in lipoprotein metabolism lead to the • Inherited defects in lipoprotein metabolism lead to a
primary condition of either hypo- or hyperlipopro- primary condition of hypo- or hyperlipoproteinemia.
teinemia (Table 26–1). In addition, diseases such as Conditions such as diabetes mellitus, hypothy-
diabetes mellitus, hypothyroidism, kidney disease roidism, kidney disease, and atherosclerosis exhibit
(nephrotic syndrome), and atherosclerosis are associ- secondary abnormal lipoprotein patterns that resem-
ated with secondary abnormal lipoprotein patterns that ble certain primary conditions.
are very similar to one or another of the primary inher-
ited conditions. Virtually all of the primary conditions REFERENCES
are due to a defect at a stage in lipoprotein formation,
transport, or destruction (see Figures 25–4, 26–5, and Illingworth DR: Management of hypercholesterolemia. Med Clin
26–6). Not all of the abnormalities are harmful. North Am 2000;84:23.

SUMMARY Ness GC, Chambers CM: Feedback and hormonal regulation of
hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase:
• Cholesterol is the precursor of all other steroids in the concept of cholesterol buffering capacity. Proc Soc Exp
the body, eg, corticosteroids, sex hormones, bile Biol Med 2000;224:8.

Parks DJ et al: Bile acids: natural ligands for a nuclear orphan re-
ceptor. Science 1999;284:1365.

Princen HMG: Regulation of bile acid synthesis. Curr Pharm De-
sign 1997;3:59.

230 / CHAPTER 26 Various authors: The cholesterol facts. A summary of the evidence
relating dietary fats, serum cholesterol, and coronary heart
Russell DW: Cholesterol biosynthesis and metabolism. Cardiovas- disease. Circulation 1990;81:1721.
cular Drugs Therap 1992;6:103.
Zhang FL, Casey PJ: Protein prenylation: Molecular mechanisms
Spady DK, Woollett LA, Dietschy JM: Regulation of plasma LDL- and functional consequences. Annu Rev Biochem 1996;
cholesterol levels by dietary cholesterol and fatty acids. Annu 65:241.
Rev Nutr 1993;13:355.

Tall A: Plasma lipid transfer proteins. Annu Rev Biochem 1995;
64:235.

Various authors: Biochemistry of Lipids, Lipoproteins and Mem-
branes. Vance DE, Vance JE (editors). Elsevier, 1996.

Integration of Metabolism— 27
The Provision of Metabolic Fuels

David A Bender, PhD, & Peter A. Mayes, PhD, DSc

BIOMEDICAL IMPORTANCE MANY METABOLIC FUELS

An adult human weighing 70 kg requires about 10–12 ARE INTERCONVERTIBLE
MJ (2400–2900 kcal) from metabolic fuels each day.
This requirement is met from carbohydrates (40–60%), Carbohydrate in excess of immediate requirements as
lipids (mainly triacylglycerol, 30–40%), protein (10– fuel or for synthesis of glycogen in muscle and liver may
15%), and alcohol if consumed. The mix being oxi- be used for lipogenesis (Chapter 21) and hence triacyl-
dized varies depending on whether the subject is in the glycerol synthesis in both adipose tissue and liver
fed or starving state and on the intensity of physical (whence it is exported in very low density lipoprotein).
work. The requirement for metabolic fuels is relatively The importance of lipogenesis in human beings is un-
constant throughout the day, since average physical ac- clear; in Western countries, dietary fat provides
tivity only increases metabolic rate by about 40–50% 35–45% of energy intake, while in less developed coun-
over the basal metabolic rate. However, most people tries where carbohydrate may provide 60–75% of en-
consume their daily intake of metabolic fuels in two or ergy intake the total intake of food may be so low that
three meals, so there is a need to form reserves of carbo- there is little surplus for lipogenesis. A high intake of fat
hydrate (glycogen in liver and muscle) and lipid (tri- inhibits lipogenesis.
acylglycerol in adipose tissue) for use between meals.
Fatty acids (and ketone bodies formed from them)
If the intake of fuels is consistently greater than en- cannot be used for the synthesis of glucose. The reac-
ergy expenditure, the surplus is stored, largely as fat, tion of pyruvate dehydrogenase, forming acetyl-CoA, is
leading to the development of obesity and its associated irreversible, and for every two-carbon unit from acetyl-
health hazards. If the intake of fuels is consistently CoA that enters the citric acid cycle there is a loss of
lower than energy expenditure, there will be negligible two carbon atoms as carbon dioxide before only one
fat and carbohydrate reserves, and amino acids arising molecule of oxaloacetate is re-formed—ie, there is no
from protein turnover will be used for energy rather net increase. This means that acetyl-CoA (and therefore
than replacement protein synthesis, leading to emacia- any substrates that yield acetyl-CoA) can never be used
tion and eventually death. for gluconeogenesis (Chapter 19). The (relatively rare)
fatty acids with an odd number of carbon atoms yield
After a normal meal there is an ample supply of car- propionyl-CoA as the product of the final cycle of β-
bohydrate, and the fuel for most tissues is glucose. In oxidation (Chapter 22), and this can be a substrate for
the starving state, glucose must be spared for use by the gluconeogenesis, as can the glycerol released by lipolysis
central nervous system (which is largely dependent on of adipose tissue triacylglycerol reserves. Most of the
glucose) and the erythrocytes (which are wholly reliant amino acids in excess of requirements for protein syn-
on glucose). Other tissues can utilize alternative fuels thesis (arising from the diet or from tissue protein
such as fatty acids and ketone bodies. As glycogen re- turnover) yield pyruvate, or five- and four-carbon in-
serves become depleted, so amino acids arising from termediates of the citric acid cycle. Pyruvate can be
protein turnover and glycerol arising from lipolysis are carboxylated to oxaloacetate, which is the primary
used for gluconeogenesis. These events are largely con- substrate for gluconeogenesis, and the five- and
trolled by the hormones insulin and glucagon. In dia- four-carbon intermediates also result in a net increase in
betes mellitus there is either impaired synthesis and the formation of oxaloacetate, which is then available
secretion of insulin (type 1 diabetes mellitus) or im- for gluconeogenesis. These amino acids are classified as
paired sensitivity of tissues to insulin action (type 2 di- glucogenic. Lysine and leucine yield only acetyl-CoA
abetes mellitus), leading to severe metabolic derange- on oxidation and thus cannot be used for gluconeogen-
ment. In cattle the demands of heavy lactation can lead esis, while phenylalanine, tyrosine, tryptophan, and
to ketosis, as can the demands of twin pregnancy in isoleucine give rise to both acetyl-CoA and to interme-
sheep. diates of the citric acid cycle that can be used for gluco-

231

232 / CHAPTER 27 rate of synthesis of glucose 6-phosphate. This is in ex-
cess of the liver’s requirement for energy and is used
neogenesis. Those amino acids that give rise to acetyl- mainly for synthesis of glycogen. In both liver and
CoA are classified as ketogenic because in the starving skeletal muscle, insulin acts to stimulate glycogen syn-
state much of the acetyl-CoA will be used for synthesis thase and inhibit glycogen phosphorylase. Some of the
of ketone bodies in the liver. glucose entering the liver may also be used for lipogene-
sis and synthesis of triacylglycerol. In adipose tissue, in-
A SUPPLY OF METABOLIC FUELS sulin stimulates glucose uptake, its conversion to fatty
IS PROVIDED IN BOTH THE FED acids, and their esterification; and inhibits intracellular
& STARVING STATES lipolysis and the release of free fatty acids.
(Figure 27–1)
The products of lipid digestion enter the circulation
Glucose Is Always Required by the Central as triacylglycerol-rich chylomicrons (Chapter 25). In
Nervous System & Erythrocytes adipose tissue and skeletal muscle, lipoprotein lipase is
activated in response to insulin; the resultant free fatty
Erythrocytes lack mitochondria and hence are wholly acids are largely taken up to form triacylglycerol re-
reliant on glycolysis and the pentose phosphate path- serves, while the glycerol remains in the blood stream
way. The brain can metabolize ketone bodies to meet and is taken up by the liver and used for glycogen syn-
about 20% of its energy requirements; the remainder thesis or lipogenesis. Free fatty acids remaining in the
must be supplied by glucose. The metabolic changes blood stream are taken up by the liver and reesterified.
that occur in starvation are the consequences of the The lipid-depleted chylomicron remnants are also
need to preserve glucose and the limited reserves of cleared by the liver, and surplus liver triacylglycerol—
glycogen in liver for use by the brain and erythrocytes including that from lipogenesis—is exported in very
and to ensure the provision of alternative fuels for other low density lipoprotein.
tissues. The fetus and synthesis of lactose in milk also
require a significant amount of glucose. Under normal feeding patterns the rate of tissue
protein catabolism is more or less constant throughout
In the Fed State, Metabolic Fuel the day; it is only in cachexia that there is an increased
Reserves Are Laid Down rate of protein catabolism. There is net protein catabo-
lism in the postabsorptive phase of the feeding cycle
For several hours after a meal, while the products of di- and net protein synthesis in the absorptive phase, when
gestion are being absorbed, there is an abundant supply the rate of synthesis increases by about 20–25%. The
of metabolic fuels. Under these conditions, glucose is increased rate of protein synthesis is, again, a response
the major fuel for oxidation in most tissues; this is ob- to insulin action. Protein synthesis is an energy-expen-
served as an increase in the respiratory quotient (the sive process, accounting for up to almost 20% of energy
ratio of carbon dioxide produced to oxygen consumed) expenditure in the fed state, when there is an ample
from about 0.8 in the starved state to near 1 (Table supply of amino acids from the diet, but under 9% in
27–1). the starved state.

Glucose uptake into muscle and adipose tissue is Metabolic Fuel Reserves Are Mobilized
controlled by insulin, which is secreted by the B islet
cells of the pancreas in response to an increased concen- in the Starving State
tration of glucose in the portal blood. An early response
to insulin in muscle and adipose tissue is the migration There is a small fall in plasma glucose upon starvation,
of glucose transporter vesicles to the cell surface, expos- then little change as starvation progresses (Table 27–2;
ing active glucose transporters (GLUT 4). These in- Figure 27–2). Plasma free fatty acids increase with
sulin-sensitive tissues will only take up glucose from the onset of starvation but then plateau. There is an initial
blood stream to any significant extent in the presence of delay in ketone body production, but as starvation pro-
the hormone. As insulin secretion falls in the starved gresses the plasma concentration of ketone bodies in-
state, so the transporters are internalized again, reduc- creases markedly.
ing glucose uptake.
In the postabsorptive state, as the concentration of
The uptake of glucose into the liver is independent glucose in the portal blood falls, so insulin secretion de-
of insulin, but liver has an isoenzyme of hexokinase creases, resulting in skeletal muscle and adipose tissue
(glucokinase) with a high Km, so that as the concentra- taking up less glucose. The increase in secretion of
tion of glucose entering the liver increases, so does the glucagon from the A cells of the pancreas inhibits
glycogen synthase and activates glycogen phosphorylase
in liver. The resulting glucose 6-phosphate in liver is

INTEGRATION OF METABOLISM—THE PROVISION OF METABOLIC FUELS / 233

Glucose 6-phosphate

Acyl-CoA Glycerol 3-phosphate

ADIPOSE
TISSUE

TRIACYLGLYCEROL (TG)
cAMP

EXTRAHEPATIC FFA Glycerol BLOOD
TISSUE (eg, LPL
heart muscle) GASTRO-
FFA Glycerol INTESTINAL
Glycerol
Chylomicrons TRACT
Oxidation LPL TG
(lipoproteins)
FFA FFA

Glucose Glucose

VLDL Extra
glucose
drain (eg,
diabetes,
pregnancy,
lactation)

Ketone bodies FFA TG Glucose

LIVER

Acyl-CoA Glycerol 3-phosphate

Acetyl-CoA Glucose 6-phosphate
Glycogen
Citric 2CO2 Gluconeogenesis
acid
cycle Amino acids,
lactate

Figure 27–1. Metabolic interrelationships between adipose tissue, the liver, and extrahepatic
tissues. In extrahepatic tissues such as heart, metabolic fuels are oxidized in the following order of
preference: (1) ketone bodies, (2) fatty acids, (3) glucose. (LPL, lipoprotein lipase; FFA, free fatty
acids; VLDL, very low density lipoproteins.)

234 / CHAPTER 27

Table 27–1. Energy yields, oxygen consumption, and carbon
dioxide production in the oxidation of metabolic fuels.

Energy Yield O2 Consumed CO2 Produced Oxygen

(kJ/g) (L/g) (L/g) RQ (kJ/L)

Carbohydrate 16 0.829 0.829 1.00 20

Protein 17 0.966 0.782 0.81 20

Fat 37 2.016 1.427 0.71 20

hydrolyzed by glucose-6-phosphatase, and glucose is re- Although muscle takes up and preferentially oxidizes
leased into the blood stream for use by other tissues, free fatty acids in the starving state, it cannot meet all of
particularly the brain and erythrocytes. its energy requirements by β-oxidation. By contrast, the
liver has a greater capacity for β-oxidation than it re-
Muscle glycogen cannot contribute directly to quires to meet its own energy needs and forms more
plasma glucose, since muscle lacks glucose-6-phos- acetyl-CoA than can be oxidized. This acetyl-CoA is
phatase, and the primary purpose of muscle glycogen is used to synthesize ketone bodies (Chapter 22), which
to provide a source of glucose 6-phosphate for energy- are major metabolic fuels for skeletal and heart muscle
yielding metabolism in the muscle itself. However, and can meet some of the brain’s energy needs. In pro-
acetyl-CoA formed by oxidation of fatty acids in muscle longed starvation, glucose may represent less than 10%
inhibits pyruvate dehydrogenase and leads to citrate ac- of whole body energy-yielding metabolism. Further-
cumulation, which in turn inhibits phosphofructoki- more, as a result of protein catabolism, an increasing
nase and therefore glycolysis, thus sparing glucose. Any number of amino acids are released and utilized in the
accumulated pyruvate is transaminated to alanine at the liver and kidneys for gluconeogenesis.
expense of amino acids arising from breakdown of pro-
tein reserves. The alanine—and much of the keto acids Plasma insulin Plasma glucagon
resulting from this transamination—are exported from
muscle and taken up by the liver, where the alanine is Relative change
transaminated to yield pyruvate. The resultant amino fattPylaascimdas free
acids are largely exported back to muscle to provide
amino groups for formation of more alanine, while the Blood glucose
pyruvate is a major substrate for gluconeogenesis in the
liver.

In adipose tissue, the effect of the decrease in insulin
and increase in glucagon results in inhibition of lipo-
genesis, inactivation of lipoprotein lipase, and activa-
tion of hormone-sensitive lipase (Chapter 25). This
leads to release of increased amounts of glycerol (a sub-
strate for gluconeogenesis in the liver) and free fatty
acids, which are used by skeletal muscle and liver as
their preferred metabolic fuels, so sparing glucose.

Table 27–2. Plasma concentrations of metabolic Blood ketone bodies Liver glycogen
fuels (mmol/L) in the fed and starving states.

40 Hours 7 Days
Fed Starvation Starvation

Glucose 5.5 3.6 3.5 0 12–24
Free fatty acids Hours of starvation
Ketone bodies 0.30 1.15 1.19
Figure 27–2. Relative changes in metabolic parame-
Negligible 2.9 4.5 ters during the onset of starvation.

Table 27–3. Summary of the major and unique features of metabolism

Organ Major Function Major Pathways Main Subst

Liver Service for the other Most represented, inclu- Free fatty acids, glu

organs and tissues ding gluconeogenesis; fed), lactate, glycer
β-oxidation; ketogenesis; amino acids
lipoprotein formation;

urea, uric acid, and bile

acid formation; choles-
terol synthesis; lipogenesis1 (Ethanol)

Brain Coordination of the Glycolysis, amino acid me- Glucose, amino aci

nervous system tabolism bodies (in starvatio

Polyunsaturated fa

in neonate

Heart Pumping of blood Aerobic pathways, eg, Free fatty acids, lac
β-oxidation and citric acid tone bodies, VLDL
cycle micron triacylglyce
glucose

Adipose tissue Storage and break- Esterification of fatty acids Glucose, lipoprote
down of triacylglyc- and lipolysis; lipogenesis1 glycerol

erol

Muscle Glucose
Fast twitch Rapid movement Glycolysis Ketone bodies, tria
Slow twitch Sustained movement Aerobic pathways, eg, in VLDL and chylom
β-oxidation and citric free fatty acids
acid cycle

Kidney Excretion and glu- Gluconeogenesis Free fatty acids, lac
coneogenesis glycerol

Erythrocytes Transport of O2 Glycolysis, pentose phos- Glucose
phate pathway. No mito-
chondria and therefore no
β-oxidation or citric acid
cycle.

1In many species but not very active in humans.

m of the principal organs.

trates Major Products Specialist Enzymes

ucose (well Glucose, VLDL (triacylglyc- Glucokinase, glucose-6-phosphatase,

rol, fructose, erol), HDL, ketone bodies, glycerol kinase, phosphoenolpyruvate

urea, uric acid, bile acids, carboxykinase, fructokinase, arginase,

plasma proteins HMG-CoA synthase and lyase, 7α-

hydroxylase

(Acetate) (Alcohol dehydrogenase)
Lactate
id, ketone
on)
atty acids

ctate, ke- Lipoprotein lipase. Respiratory chain
and chylo- well developed.
erol, some

ein triacyl- Free fatty acids, glycerol Lipoprotein lipase, hormone-sensitive
lipase

Lactate Lipoprotein lipase.
acylglycerol Respiratory chain well developed.
microns,
Glycerol kinase, phosphoenolpyruvate
ctate, Glucose carboxykinase
(Hemoglobin)
Lactate

236 / CHAPTER 27 A summary of the major and unique metabolic fea-
tures of the principal tissues is presented in Table 27–3.
CLINICAL ASPECTS
SUMMARY
In prolonged starvation, as adipose tissue reserves are
depleted there is a very considerable increase in the net • The body can interconvert the majority of foodstuffs.
rate of protein catabolism to provide amino acids not However, there is no net conversion of most fatty
only as substrates for gluconeogenesis but also as the acids (or other acetyl-CoA-forming substances) to
main metabolic fuel of the tissues. Death results when glucose. Most amino acids, arising from the diet or
essential tissue proteins are catabolized beyond the from tissue protein, can be used for gluconeogenesis,
point at which they can sustain this metabolic drain. In as can the glycerol from triacylglycerol.
patients with cachexia as a result of release of cytokines
in response to tumors and a number of other patho- • In starvation, glucose must be provided for the brain
logic conditions, there is an increase in the rate of tissue and erythrocytes; initially, this is supplied from liver
protein catabolism as well as a considerably increased glycogen reserves. To spare glucose, muscle and other
metabolic rate, resulting in a state of advanced starva- tissues reduce glucose uptake in response to lowered
tion. Again, death results when essential tissue proteins insulin secretion; they also oxidize fatty acids and ke-
have been catabolized. tone bodies preferentially to glucose.

The high demand for glucose by the fetus and for • Adipose tissue releases free fatty acids in starvation,
synthesis of lactose in lactation can lead to ketosis. This and these are used by many tissues as fuel. Further-
may be seen as mild ketosis with hypoglycemia in more, in the liver they are the substrate for synthesis
women, but in lactating cattle and in ewes carrying of ketone bodies.
twins there may be very pronounced ketosis and pro-
found hypoglycemia. • Ketosis, a metabolic adaptation to starvation, is exac-
erbated in pathologic conditions such as diabetes
In poorly controlled type 1 diabetes mellitus, pa- mellitus and ruminant ketosis.
tients may become hyperglycemic, partly as a result of
lack of insulin to stimulate uptake and utilization of REFERENCES
glucose and partly because of increased gluconeogenesis
from amino acids in the liver. At the same time, the Bender DA: Introduction to Nutrition and Metabolism, 3rd edition.
lack of insulin results in increased lipolysis in adipose Taylor & Francis, 2002.
tissue, and the resultant free fatty acids are substrates
for ketogenesis in the liver. It is possible that in very se- Caprio S et al: Oxidative fuel metabolism during mild hypo-
vere diabetes utilization of ketone bodies in muscle glycemia: critical role of free fatty acids. Am J Physiol
(and other tissues) is impaired because of lack of ox- 1989;256:E413.
aloacetate (most tissues have a requirement for some
glucose metabolism to maintain an adequate amount of Fell D: Understanding the Control of Metabolism. Portland Press,
oxaloacetate for citric acid cycle activity). In uncon- 1997.
trolled diabetes, the magnitude of ketosis may be such
as to result in severe acidosis (ketoacidosis) since ace- Frayn KN: Metabolic Regulation—A Human Perspective. Portland
toacetic acid and 3-hydroxybutyric acid are relatively Press, 1996.
strong acids. Coma results from both the acidosis and
the considerably increased osmolarity of extracellular McNamara JP: Role and regulation of metabolism in adipose tissue
fluid (mainly due to the hyperglycemia). during lactation. J Nutr Biochem 1995;6:120.

Randle PJ: The glucose-fatty acid cycle—biochemical aspects. Ath-
erosclerosis Rev 1991;22:183.

SECTION III

Metabolism of Proteins & Amino Acids

Biosynthesis of the Nutritionally 28
Nonessential Amino Acids

Victor W. Rodwell, PhD

BIOMEDICAL IMPORTANCE those three enzymes is to transform ammonium ion
into the α-amino nitrogen of various amino acids.
All 20 of the amino acids present in proteins are essential
for health. While comparatively rare in the Western Glutamate and Glutamine. Reductive amination of
world, amino acid deficiency states are endemic in cer- α-ketoglutarate is catalyzed by glutamate dehydrogenase
tain regions of West Africa where the diet relies heavily (Figure 28–1). Amination of glutamate to glutamine is
on grains that are poor sources of amino acids such as catalyzed by glutamine synthetase (Figure 28–2).
tryptophan and lysine. These disorders include kwash-
iorkor, which results when a child is weaned onto a Alanine. Transamination of pyruvate forms alanine
starchy diet poor in protein; and marasmus, in which (Figure 28–3).
both caloric intake and specific amino acids are deficient.
Aspartate and Asparagine. Transamination of
Humans can synthesize 12 of the 20 common amino oxaloacetate forms aspartate. The conversion of aspartate
acids from the amphibolic intermediates of glycolysis and
of the citric acid cycle (Table 28–1). While nutritionally Table 28–1. Amino acid requirements
nonessential, these 12 amino acids are not “nonessential.” of humans.
All 20 amino acids are biologically essential. Of the 12 nu-
tritionally nonessential amino acids, nine are formed from Nutritionally Essential Nutritionally Nonessential
amphibolic intermediates and three (cysteine, tyrosine
and hydroxylysine) from nutritionally essential amino Arginine1 Alanine
acids. Identification of the twelve amino acids that hu- Histidine Asparagine
mans can synthesize rested primarily on data derived from Isoleucine Aspartate
feeding diets in which purified amino acids replaced pro- Leucine Cysteine
tein. This chapter considers only the biosynthesis of the Lysine Glutamate
twelve amino acids that are synthesized in human tissues, Methionine Glutamine
not the other eight that are synthesized by plants. Phenylalanine Glycine
Threonine Hydroxyproline2
NUTRITIONALLY NONESSENTIAL Tryptophan Hydroxylysine2
Valine Proline
AMINO ACIDS HAVE SHORT Serine
Tyrosine
BIOSYNTHETIC PATHWAYS
1“Nutritionally semiessential.” Synthesized at rates inadequate
The enzymes glutamate dehydrogenase, glutamine syn- to support growth of children.
thetase, and aminotransferases occupy central positions 2Not necessary for protein synthesis but formed during post-
in amino acid biosynthesis. The combined effect of translational processing of collagen.

237

238 / CHAPTER 28

–O O –O NH3+ O– O O– NH3+ O–
O– Pyruvate O Alanine

OO OO O
α-Ketoglutarate L-Glutamate

NH4+ H2O Glu or Asp α-Ketoglutarate or oxaloacetate

NAD(P)H + H+ NAD(P)+ Figure 28–3. Formation of alanine by transamina-
tion of pyruvate. The amino donor may be glutamate or
Figure 28–1. The glutamate dehydrogenase aspartate. The other product thus is α-ketoglutarate or
reaction. oxaloacetate.

to asparagine is catalyzed by asparagine synthetase (Fig- O NH 3 + O NH +
ure 28–4), which resembles glutamine synthetase (Fig- –O O– H2N 3
ure 28–2) except that glutamine, not ammonium ion, O–
provides the nitrogen. Bacterial asparagine synthetases
can, however, also use ammonium ion. Coupled hy- O O
drolysis of PPi to Pi by pyrophosphatase ensures that
the reaction is strongly favored. L-Aspartate L-Asparagine

Serine. Oxidation of the α-hydroxyl group of the Gln Glu
glycolytic intermediate 3-phosphoglycerate converts it
to an oxo acid, whose subsequent transamination and Mg-ATP Mg-AMP + PPi
dephosphorylation leads to serine (Figure 28–5).
Figure 28–4. The asparagine synthetase reaction.
Glycine. Glycine aminotransferases can catalyze the Note similarities to and differences from the glutamine
synthesis of glycine from glyoxylate and glutamate or synthetase reaction (Figure 28–2).
alanine. Unlike most aminotransferase reactions, these
strongly favor glycine synthesis. Additional important
mammalian routes for glycine formation are from
choline (Figure 28–6) and from serine (Figure 28–7).

Proline. Proline is formed from glutamate by rever-
sal of the reactions of proline catabolism (Figure 28–8).

Cysteine. Cysteine, while not nutritionally essen-
tial, is formed from methionine, which is nutritionally
essential. Following conversion of methionine to ho-

OH NADH O
O− O−

PO O PO O
D-3-Phosphoglycerate Phosphohydroxy

NH3+ NH3+ pyruvate

α-AA

–O O– H2N O–

α-KA

OO OO NH3+ Pi H2O NH3+
L-Glutamate L-Glutamine O− O−

NH4+ HO O PO O
L-Serine Phospho-L-serine
Mg-ATP Mg-ADP + Pi

Figure 28–2. The glutamine synthetase reaction. Figure 28–5. Serine biosynthesis. (α-AA, α-amino
acids; α-KA, α-keto acids.)