lipid metabolism

Metabolism II:

Lipids

Topic At the end of the topic, the students should be able to:
Learning
Outcomes •identify the main metabolic pathways of lipids and

the importance of the pathways

•differentiate between the different metabolic
pathways

•identify the steps which produced and used ATP,

NADH, FADH2, NADPH

Fats from diet Bile salts

TAG emulsion Intestinal lumen
pancreatic lipase

2 fatty acids Monoacylglycerol (MAG)

Digestion and 2 fatty acids 2 CoA Enterocyte of
Absorption of intestinal wall
Triacylglycerols (TAG) MG
Lymph duct
2 fatty acyl-CoAs TG
Protein
Chylomicrons

Chylomicrons

Main Metabolic Pathways of Lipids

Triacylglycerol

Lipogenesis Lipolysis

Fatty Acids

Fatty Acid Synthesis β-oxidation

Acetyl Co-A Ketone Bodies

Ketogenesis

Lipolysis •degradation of TAG when energy resource is low 

during fasting, vigorous exercise and in response to
stress

•involves glucagon and epinephrine:

attached to specific receptor on adipose tissue plasma
membrane initiating reaction cascade

 level of cytosolic cAMP and activate hormone-
sensitive TAG lipase

•fatty acids and glycerol produced are secreted into

blood system

Lipolysis reaction cascade

•glycerol is transported to liver for lipid or
glucose synthesis

• fates of fatty acids:

attached to serum albumin and transported
to tissues for energy

degradation via β-oxidation pathway used
in synthesis of TAG

used in membrane synthesis

Fatty Acids •fatty acids are degraded by sequential
-Oxidation
removal of 2C fragments from the carboxyl
end  acetyl-coA is formed; link between
- and -C is broken; -C is oxidized

• occurs in the mitochondrial matrix (and

also in peroxisome) of liver, muscle and
heart cells

•1st step  fatty acid activation,

forming acyl-CoA

•occurs in cytosol
•catalyzed by acyl-CoA synthetase

• 2nd step  transportation Carnitine
of activated fatty acids (i.e. acyltransferase I
acyl-CoA) into
mitochondrial matrix from Carnitine
the cytosol acyltransferase II

• 3rd step  -oxidation process (for saturated fatty acids with even-numbered chain) :

Dehydrogenation
Hydration
Oxidation
Thiolysis

•e.g. palmitic acid (16:0) undergoes 7 cycles:

products  7 FADH2, 7 NADH, 8 acetyl-CoA
uses  2 ATP (during activation)

therefore, ATP/energy produced:

Complete 7 FADH2 x 2 ATP/FADH2 14 ATP
oxidation of a 7 NADH x 3 ATP/NADH 21 ATP

fatty acid 8 Acetyl-CoA x 12 ATP/acetyl-CoA 96 ATP

Uses 2 ATP - 2 ATP

Amount of ATP produced: 129 ATP

(or 129/16 = 8.1 ATP/C atom)

For an even-numbered saturated
fat (C2n) the total yield of ATP
follows this formula:

(n-1) * 17 + 12 - 2

-oxidation in • shorten a very long fatty Acyl-coA
acids, some long chain fatty synthetase
peroxisome acids, & long chain
dicarboxylic acids Acyl-coA
oxidase
 acyl-coA synthetase that is
specific for very long-chain Enoyl-coA
fatty acids hydratase

• resulting medium chain fatty Hydroxyacyl-coA
acids (i.e. 6-12 carbons) are dehydrogenase
further degraded in
mitochondria -keto
thiolase

•reactions are the same as mitochondrial -
oxidation but with notable differences:
initial reaction catalyzed by different enzyme 
acyl-coA oxinidsatesaed; FoAfDCHoQ2 d(ofonraAteTsPe)- to oxygen
enoyl-CoA hydratase and hydroxyacyl CoA
dehydrogenase of the peroxisomal pathway are
found on the same protein
-keto thiolase of peroxisomal pathway has a
different substrate specificity  doesn’t efficiently
bind medium-chain acyl-CoA

• unsaturated fatty acids  needs additional
enzymes (e.g. enoyl-CoA isomerase and 2,4-
dienoyl-CoA reductase)

Oxidation of other •odd-chain fatty acids  same as even-chain
types of fatty acids fatty acids but in the last step, produced 1
acetyl-CoA + 1 propionyl-CoA (converted into
succinyl co-A)

•branched fatty acids  -oxidation

C18 , cis,cis-9,12 Unsaturated fatty
C12 , cis,cis-3,6 acids oxidation
(e.g. linoleic acid,
C12 , trans,cis-2,6 18:2(9,12)):
C10, trans,cis-2,4
C10 , trans-3 C10 , trans-2

Complete oxidation of an unsaturated fatty acids
(e.g. linoleic acid, 18:2(9,12))

 if without double bonds:
(8 x 17) + 12 - 2 = 146 ATP

8 cycles of -oxidation Final acetyl-coA Activation
product

 however, due to the cis-double bonds:

(3 x 17) + 15 + (4 x 17) + 12 - 2 - 3 = 141 ATP

3 cycles of -oxidation 4 cycles of -oxidation Activation

4th cycle Final acetyl-coA product Reductase

• in summary:

 for odd-numbered double bonds:
 handled by isomerase
 costs 2 ATP

 for even-numbered double bonds:
 handled by reductase and isomerase

 costs 3 ATP (from NADPH)

Odd-chain fatty acids

Odd-chain -oxidation
fatty acids
oxidation Acetyl-CoA
+

Propionyl-CoA

cont’d next slide…

cont’d from previous slide… Succinyl-coA

Succinyl-coA synthetase GTP 1 ATP
2 ATP
Succinate
3 ATP
Succinate dehydrogenase FADH2 12 ATP

Fumarate

Fumarase

Malate

Malic enzyme NADPH

Pyruvate

Pyruvate dehydrogenase NADH

Acetyl-coA

Complete oxidation of an odd-numbered fatty acids

Add 5 ATP from the last cycle (i.e. from
propionyl-coA to succinyl-coA to acetyl-

coA):

(n-1)*17 + 6 + 12 - 2 - 1

(n-1) -oxidation Final acetyl-coA From propionyl-coA to
cycles product methylmalonyl-coA

From succinyl-coA to Activation
acetyl-coA

H2O PhPyhtyatnainciaccaicdid
Phytanic acid -hydroxylase

Branched fatty -hydroxyphytanic acid -hydroxyphytanic acid
acids oxidation Phytanic acid -oxidase CO2

(e.g. -oxidation of

phytanic acid)

PrPirsitsatnainciaccaicdid 6 cycles of -
oxidation

generating 3
acetyl-CoA, 3
propionyl-CoA & 1
isobutyl-CoA

Ketone Bodies •when level of acetyl CoA from β-oxidation increases
Formation in excess, acetyl CoA is converted to ketone bodies
 i.e. acetoacetate, β-hydroxybutyrate, acetone

•produced in ketogenesis process in liver
mitochondria

•ketosis  when level of blood acetone is high; in
untreated diabetics – smell of acetone on their
breath

Ketogenesis process

•ketone bodies: source of energy for some
tissues (e.g. brain, heart, muscle) when starved
or in diabetics:

β-hydroxybutyrate

NAD+ β-hydroxybutyrate dehydrogenase
NADH + H+

Acetoacetate

Succinyl-CoA β-ketoacyl-CoA transferase
Succinate

Acetoacetyl-CoA

Co-ASH Co-ASH Acetyl-CoA thiolase

2 Acetyl-CoA

ATP produced from oxidation of ketone bodies

 2 sources:

 -hydroxybutyrate:

1 NADH X 3 ATP/NADH 3 ATP
24 ATP
2 Acetyl-CoA X 12 ATP/acetyl-CoA - 1 ATP

Use 1 GTP/ATP in transfer of CoA from 26 ATP
succinyl-CoA to acetoacetate
Amount of ATP produced:

 acetoacetate:

Calculation is the same as above but no NADH produced,
therefore only 23 ATP are formed from acetoacetate

Lipogenesis •process by which acetyl-CoA is converted to

fats

•energy can be efficiently stored in the form

of fats

•includes the processes of fatty acid synthesis

and subsequent TAG synthesis

Fatty Acid •occurs in cytosol of liver cells, adipocytes and
Synthesis specialized cells

•NOT a reverse of oxidation process
•divided into 3 stages:

 transportation of acetyl-CoA from
mitochondria into cytosol

 acetyl-CoA carboxylation
 fatty acids synthesis reactions  by fatty acid

synthase complex

Differences between fatty acids oxidation and synthesis

Comparison between Degradation Biosynthesis
fatty acid degradation
Product is Acetyl-CoA Precursor is Acetyl-CoA
and biosynthesis
Malonyl-CoA is not involved; no Malonyl-CoA is source of 2-carbon units;
requirement for biotin biotin required

Oxidative process; requires NAD+ and Reductive process; requires NADPH and
FAD and produces ATP ATP

Fatty acids form thioesters with CoA-SH Fatty acids form thioesters with acyl-
carrier protein (ACP-SH)
Starts at carboxyl end (CH3CO2-)
Occurs in the mitochondrial matrix (or Starts at methyl end (CH3CH2-)
peroxisome), with no ordered aggregates Occurs in the cytosol, catalyzed by an
of enzymes ordered multienzyme complex

-hydroxyacyl intermediates have the L- -hydroxyacyl intermediates have the D-
configuration configuration

• acetyl-CoA comes from fatty acids oxidation or citric acid

cycle

• acetyl-CoA is transported through tricarboxylate transport
system (or citrate transport system) in citrate form :

Transportation
of acetyl-CoA

• catalyzed by acetyl-CoA carboxylase (using biotin as
cofactor) in a 2-step reaction:

Acetyl-CoA
carboxylation

Fatty acid • creating fatty acids from acetyl-CoA and malonyl Co-A
synthesis
reactions precursors through action of an enzyme called fatty acid
synthase

• elongated fatty acid is anchored at acyl carrier protein

(ACP)

Phosphopantetheine group of coenzyme A

Phosphopantetheine prosthetic group of ACP

• fatty acid synthase action  the loading step:

12
3

Step 2 – transfer of malonyl-CoA to ACP
Step 3 – transfer of acetyl-CoA to ACP

 fatty acid Acetyl-ACP
synthase
action  Malonyl-ACP (4)
successive
rounds of (5)

condensation (6)
(4), reduction (7)

(5),
dehydration

(6) and
reduction (7)

reactions

• involves 7 enzymatic activities; end product is palmitic acid
(16:0)

Fatty acid
synthase
complex

The Mammalian Fatty Acid Synthase

•for synthesis of palmitic acid:

requires 7 cycles
in the second cycle, butyryl-ACP reacts with one more

malonyl-CoA and produces hexanoyl-ACP
 end product of the 7th cycle, palmitoyl-ACP undergoes
hydrolysis by palmitoyl thioesterase (7th enzyme) palmitic

acid and free ACP

Net equation of palmitic acid synthesis

Palmitic acid synthesis:
Acetyl-CoA + 7 Malonyl-CoA + 14 NADPH + 20H+ 
Palmitic acid + 7 CO2 + 14 NADP+ + 8 CoA + 6 H2O

Since 7 malonyl-CoA are produced from acetyl-CoA:
7 Acetyl-CoA + 7 CO2 + 7 ATP 
7 Malonyl-CoA + 7 ADP + 7 Pi + 7 H+

 Complete biosynthesis of palmitic acid:
8 Acetyl-CoA + 14 NADPH + 7 ATP + 13 H+ 
Palmitic acid + 14 NADP+ + 8 CoA + 6 H2O + 7 ADP + 7 Pi

Elongation and •further elongation and desaturation processes for
desaturation of fatty acids with carbon chain longer than 16 and to
insert double bonds, respectively
fatty acids
•elongation

occurs in endoplasmic reticulum (ER) and
mitochondria

•desaturation

occurs in ER membrane

Elongation process in ER

 a predominant process resembling that catalyzed by fatty acyl synthase,
but the individual activities is on separate enzymes (not part of
multifunctional enzymes); malonyl CoA is the source of the added carbons;
no ACP is involved; CoA esters are used directly

Elongation process in mitochondria

involves the -oxidation pathway running in reverse except
that 1 NADPH and 1 NADH required; acts primarily on fatty
acyl with shorter than 16C; acetyl CoA is the source of the
added carbons

Desaturation of •fatty acyl-CoA desaturase  introduces double bond at
fatty acids
C4, C5, C6 or C9 (mammals cannot synthesize fatty acids
with double bonds more than C9 (i.e. essential fatty
acids))

• involves following ER membrane proteins (in

mammals):

NADH-cyt b5 reductase

cytochrome b5

desaturase

•4 e- reduction of O2 to form 2H2O:

2e- transferred from NADH to FAD (of reductase) to cyt
b5 to desaturase

2 e- extracted from fatty acid as double bond formed

Desaturase system of fatty acid

e.g. desaturation of stearic acid (18:0) to oleic acid (18:1)

Palmitate Synthesis of other
16:0
Desaturase polyunsaturated fatty

Palmitoleate Elongase acids

16:1(9) Stearate
18:0
Desaturase
Permitted
Oleate
18:1(9) transitions
Essential Desaturase in mammals
fatty acid
Linoleate
Desaturase 18:2(9,12)
-Linolenate
-Linolenate Desaturase
18:3(6,9,12)
18:3(9,12,15) Elongase
Eicosatrienoate
Desaturase 20:3(8,11,14)
Other lipids Arachidonate

20:4(5,8,11,14)

Regulation of •presence of substrates, allosteric effectors,
Fatty Acids enzyme modification
Metabolism
•major point of control of β-oxidation is the
availability of fatty acids

•key enzyme in the regulation of fatty acid
synthesis is acetyl-CoA carboxylase which
synthesizes malonyl-CoA

•acetyl-CoA carboxylase  rate-limiting step in synthesis

act. is inactivated by phosphorylation, catalyzed by
AMP-activated protein kinase

high AMP:ATP ratio, kinase is activated to
phosphorylate enzyme, enzyme is inactivated, fatty acid

synthesis is off
subject to hormonal regulation
 when energy is required, glucagon/epinephrine
inactivates enzyme, synthesis decreased
 when blood glucose levels are high (well-fed state),
insulin stimulates enzyme, synthesis increases

allosteric regulation
activated by citrate, inhibited by

palmitoyl-CoA
acetyl-CoA and ATP are high → citrate is

high, acetyl-CoA carboxylase is
stimulated, synthesis is activated
(excess acetyl-CoA is stored as fatty

acids)
high level of palmitoyl-CoA (meaning
excess of fatty acids), enzyme activity is

reduced, synthesis is off

Triacylglycerol •synthesized from fatty acyl CoAs and
Synthesis glycerol 3-phosphate

•ATP is not involved; reactions are driven by
cleavage of high-energy thioester bond
between acyl moiety and CoA

•phosphatidic acid and diacylglycerol
produced are also used in synthesis of
membrane phospholipids

DHAP acyltransferase

acyl-DHAP reductase

acyltransferase Synthesis of
Triacylglycerols

phosphatidic acid phosphatase
acyltransferase