Lipid Metabolism: © 2018 Cengage Learning. All Rights Reserved

Chapter 21
Lipid Metabolism
© 2018 Cengage Learning. All Rights Reserved.

Chapter Outline
(21-1) Lipids involved in generation and storage of
energy
(21-2) Catabolism of lipids
(21-3) The energy yield from oxidation of fatty
acids
(21-4) Catabolism of odd-carbon and unsaturated fatty
acids
(21-5) Ketone bodies

Chapter Outline (continued)
(21-6) Fatty acid biosynthesis
(21-8) Cholesterol biosynthesis

1. Lipids involved in generation and
storage of energy

Lipids
• In Chapter 16 we saw that there are carbohydrate
polymers such as starch and glycogen that represent
stored energy, in the sense that these carbohydrates
can be hydrolyzed to monomers and then oxidized to
provide energy
• The metabolic oxidation of lipids releases large
quantities of energy through production of acetyl-
CoA, NADH, and FADH2
• Lipids represent an even more efficient way of storing
chemical energy than carbohydrates

Fats converted  triacylglycerol molecules  widely used to
• store excess energy for later use and
• fulfill other purposes (Ex: insulating blubber of whales)
• Hydrophobic nature of fatty acids allows close packing in

adipose tissue
• Natural tendency of fats to exist in nearly water-free forms
makes fats well suited to energy storage

2. Catabolism of Lipids
• Many mammals, such as this

house mouse, hibernate
over long winter months
• Although their metabolism
slows during hibernation,
energy needs of animal must
still be met
Fatty acid degradation is a key energy source

Lipid Metabolism
• Fatty acids are stored in adipose tissue
as triacylglycerols (TAG) in which fatty
acids are linked to glycerol with ester
linkages
~95% of energy from TAG molecule from
fatty acid chains
• Adipose tissue is located throughout the

body, with subcutaneous (below the skin)
and visceral deposits (around the internal
organs) being most prominent
Fatty acids incorporated into triacylglycerols in
adipose tissue are made accessible in three stages:
1. Degradation of TAG to release fatty acids and

glycerol into the blood for transport to energy-
requiring tissues
2. Activation of the fatty acids and transport into the

mitochondrial matrix for oxidation
3. Degradation of the fatty acids to acetyl CoA for

processing by the citric acid cycle in mitochondrial
matrix

Catabolism of Lipids
• In catabolism of lipids, oxidation of fatty acids is chief
source of energy
• Triacylglycerols - Main storage form of the chemical
energy of lipids for most organisms
• Carbon chains are in a highly reduced form
• Energy yield per gram of fatty acid oxidized is greater
than that per gram of carbohydrate oxidized
• Phosphoacylglycerols - Key component of
biological membranes and also have fatty acids as
part of their covalently bonded structures

Catabolism of Lipids
• Several phospholipases hydrolyze phosphoacylglycerols.
Phospolipases designated A1, A2, C, and D (sites of action
shown; site of action of phospholipase A2 is B site, and
name phospholipase A2 is result of historical accident)
Figure 21.2
Catabolism of Lipids (continued)
• Triacylglycerols and phosphoacylglycerols
• Have fatty acids as part of their covalently bonded
structures
• Bond between the fatty acid and the rest of the
molecule can be hydrolyzed:
Lipases: Hydrolyze lipids
Phospholipases: Hydrolyze phospholipids

Catabolism of Lipids (continued)
Figure 21.1 - Release of Fatty Acids for Future Use
• The source of fatty acids can be a triacylglycerol (left)
or a phospholipid such as phosphatidylcholine (right)

Figure 21.3 - Liberation of Fatty Acids (FAs) from
Triacylglycerols in Adipose Tissue Is Hormone-Dependent
Release of FAs from triacylglycerols
in adipocytes is controlled by
hormones
Hormone binds to receptor on

plasma membrane of adipocyte
Hormone binding activates adenylate

cyclase which leads to prod’n of
active protein kinase A
Protein kinase phosphorylates

triacylyglycerol lipase which cleaves
the FAs from glycerol backbone
Main hormone that has this effect is

epinephrine; caffeine mimics
epinephrine in this regard
Fatty Acid Activation
• Fatty acid oxidation begins with activation of the
molecule
• Activation in lipid metabolism: Thioester bond is
formed between the carboxyl group of the fatty acids
and the thiol group of CoA-SH
• Acyl-CoA synthetase catalyzes formation of the ester
bond and requires ATP for its action
• Esterification takes place in cytosol, but rest of
reactions of fatty acid oxidation occur in
mitochondrial matrix
• Acyl-CoA can cross outer mitochondrial membrane
but not inner membrane
Figure 21.4 - Formation of an Acyl-CoA
Fatty Acid
Coenzyme A
• Reaction rendered irreversible by action of pyrophosphatase

(metabolic motif)

Coenzyme A
- activated carrier of acyl groups
Derived from Vitamin B5

In egg yolk, chicken, beef, broccoli

Acetyl CoA
• Fuel for citric acid cycle
• Formed by pyruvate dehydrogenase
complex
• Formed by fatty acid oxidation (aka b-
oxidation of FAs

Fatty Acid Activation (continued)
• Need “ticket” to get into mitochondrial matrix
• “Ticket” is carnitine
• Acyl group is transferred to carnitine, carried across
the inner mitochondrial membrane, and transferred to
mitochondrial CoA-SH by transesterification reactions
• Carnitine: Molecule used in fatty acid metabolism to
shuttle acyl groups across the inner mitochondrial
membrane

Fatty Acid Activation (continued)
• Transesterification reactions are catalyzed by:
• Carnitine acyltransferase, which transfers a fatty
acyl group to carnitine
• Often called carnitine palmitoyltransferase (CPT-I),
which is found on cytosol side of inner mitochondrial
membrane with a specificity for acyl groups between
14 and 18 carbons long
• Second Carnitine acyltransferase called Carnitine
palmitoyltransferase (CPT-II), which is found in
mitochondrial matrix

Figure 21.5 - Role of Carnitine in the Transfer of
Acyl Groups to the Mitochondrial Matrix
carnitine translocase,
enzyme that moves acyl-
carnitines across IM

-Oxidation
• Repeated series of reactions that cleaves two-carbon
units from the carboxyl end of a fatty acid
• Requires four reactions
1. Oxidation of acyl-CoA to ,  unsaturated acyl-CoA,
catalyzed by FAD-dependent acyl-CoA
dehydrogenase
2. Hydration of unsaturated acyl-CoA to produce a -
hydroxyacyl-CoA, catalyzed by enoyl-CoA hydratase
3. Oxidation reaction, catalyzed by -hydroxyacyl-CoA
dehydrogenase, which is an NAD+-dependent
enzyme
4. Cleavage of the -ketoacyl-CoA, catalyzed by
thiolase
-Oxidation

Figure 21.6 - -Oxidation of Saturated Fatty Acids
Involves a Cycle of Four Enzyme-Catalyzed Reactions
Each cycle produces activated
one FADH2 and one
NADH, and it liberates
acetyl-CoA, resulting in
a fatty acid that is two
carbons shorter
Δ symbol represents a double bond,

and number associated with it is
location of double bond (based on
counting the carbonyl group as
© 2018 Cengage Learning. All Rights Reserved. carbon 1)
Figure 21.7 - Stearic Acid (18 Carbons) Gives Rise to
Nine 2-Carbon Units after Eight Cycles of β-Oxidation
• The ninth 2-carbon unit remains esterified to CoA after eight cycles of β-
oxidation have removed eight successive 2-carbon units, starting at carboxyl
end on right
• Thus, it takes only eight rounds of β-oxidation to completely process an 18-
carbon fatty acid to acetyl-CoA

3. The Energy Yield from
Oxidation of Fatty Acids

Energy Yield from Oxidation of Fatty Acids
• Energy released by oxidation of acetyl-CoA formed
by -oxidation of fatty acids can be used to produce
ATP
• Eight cycles of -oxidation are required for oxidation
of one mole of stearic acid (18 carbons) to nine
moles of acetyl-CoA

Energy Yield from Oxidation of Fatty Acids
(continued)
• Nine moles of acetyl-CoA produced from each mole

of stearic acid enter citric acid cycle
• FADH2 and NADH produced by b-oxidation and

citric acid cycle enter electron transport chain, and
ATP is produced by oxidative phosphorylation
• Overall equation for oxidation of stearic acid can be
obtained by adding equations for b-oxidation, citric
acid cycle, and oxidative phosphorylation
Table 21.1 - Balance Sheet for Oxidation of
One Molecule of Stearic Acid

What is metabolic water?
• In aerobic metabolism, metabolic water is water
produced in oxidation of FAs and in complete
oxidation of carbohydrates; sometimes it is only water
source of desert-dwelling organisms
Ex: Camels - stored lipids
in their humps are a source
of both energy and water
during long trips through
the desert
desert rodent- kangaroo rat © 2018 Cengage Learning. All Rights Reserved.
4. Catabolism of odd-carbon and
unsaturated fatty acids

Oxidation of Odd-Carbon Fatty Acids
• Fatty acids with odd
number of carbon
atoms
• Odd-numbered FAs
not frequently
encountered in
nature but undergo -
oxidation
• Last -oxidation cycle
of these fatty acids
gives propionyl-CoA

Oxidation of Monounsaturated Fatty Acids
• Cis-trans isomerization is needed to
convert monounsaturated FAs to
acetyl-CoA
• Oxidation of unsaturated FAs does not
generate as many ATPs when
compared to saturated FAs with same
number of carbons
• In case of oleoyl-CoA, three β-oxidation
cycles produce three molecules of
acetyl-CoA and leave cis-Δ3-
dodecenoyl-CoA
• Rearrangement of enoyl-CoA
isomerase gives trans-Δ2 species,
which then proceeds normally through
β-oxidation pathway
Figure 21.10 - Oxidation Pathway for Polyunsaturated
Fatty Acids, Illustrated for Linoleic Acid
• Three cycles of β-oxidation on linoleoyl-

CoA yield cis-Δ3, cis-Δ6 intermediate,
which is converted to a trans-Δ2, cis-Δ6
intermediate
• An additional round of β-oxidation gives
cis-Δ4 enoyl-CoA, which is oxidized to
trans-Δ2, cis-Δ4 species by acyl-CoA
dehydrogenase
• Subsequent action of 2,4-dienoyl-CoA
reductase yields trans-Δ3 product, which
is converted by enoyl-CoA isomerase to
trans-Δ2 form
• Normal β-oxidation then produces five
molecules of acetyl-CoA
5. Ketone Bodies

Ketone Bodies
• Formed when amount of acetyl-CoA produced is
excessive when compared to amount of oxaloacetate
available to react with it
• Starvation causes an organism to break down fats for
energy, leading to production of large amount of
acetyl-CoA by -oxidation
• In diabetic patients, cause of imbalance is not
inadequate intake of carbohydrates but rather inability
to metabolize them
• High intake of lipids and a low intake of carbohydrates
can lead to high acetyl-CoA and formation of ketone
bodies
Ketone Bodies
• Formed principally in liver mitochondria
• Ketone bodies:
1. Acetone
2. -hydroxybutyrate
3. Acetoacetate
• Acetoacetate can be used as a fuel in most
tissues and organs

Figure 21.11 - Formation of Ketone Bodies,
Synthesized Primarily in the Liver
can be used as a fuel in

most tissues and organs
 2 acetylCoA
Ketone Bodies
Odor of acetone can be detected
on breath of people with untreated
diabetes
6. Fatty Acid
Biosynthesis

Fatty Acid Biosynthesis
• Anabolism is not exact reversal of reactions of β-
oxidation
• Begins with acetyl-CoA
• Acetyl-CoA can be formed either:
1. by β-oxidation of fatty acids -or-
2. by decarboxylation of pyruvate
• Fatty Acid biosynthesis takes place in cytosol
• But acetyl-CoA is produced mainly in mitochondria
from catabolism of fatty acids and carbohydrates

Fatty Acid Biosynthesis
Three stages:
1. Transfer of acetyl CoA out of mitochondria into
cytoplasm
• Acetyl-CoA condenses with oxaloacetate to
form citrate
• Citrate is transported into cytoplasm and
cleaved into oxaloacetate and acetyl CoA
2. Activation of acetyl CoA to form malonyl CoA
3. Repetitive addition and reduction of two carbon
units to synthesize C16 fatty acid; synthesis
occurs on an acyl carrier protein, a molecular
scaffold
Stage 1: Transfer
Fatty Acid Biosynthesis (continued)
• Indirect transfer mechanism involves citrate
• Citrate is transported from mitochondria into
cytoplasm and cleaved into oxaloacetate and acetyl-
CoA
• Oxaloacetate that is formed provides a means for
the production of the NADPH needed for
biosynthesis
Citrate + CoA - SH + ATP  Acetyl - CoA + Oxaloacetate + ADP + Pi

ATP-citrate lyase

Lipid Anabolism (continued)
• Net effect of these two reactions is replacement of

NADH by NADPH
• While there is some NADPH produced by this means,
its principal source is pentose phosphate pathway

Figure 21.13 - Transport of Acetyl Groups from
the Mitochondrion to the Cytosol
Citrate that is exported

to cytosol can undergo
the reverse reaction
producing OAA and
acetyl-CoA
Acetyl-CoA enters
pathway for fatty acid
biosynthesis
OAA undergoes a
series of reactions in
which NADPH is
substituted for NADH

Stage 2: Activation
Fatty Acid Biosynthesis (continued)
• Carboxylation of acetyl-CoA in the cytosol
• Catalyzed by acetyl-CoA carboxylase complex,
which requires Mn2+, biotin, and ATP
• Biotin - Carrier of the carboxyl group and an important
cofactor in the reaction
• Produces key three-carbon intermediate in FA
biosynthesis, malonyl-CoA

Figure 21.15 - Acetyl-CoA Carboxylase Reaction
(a) The acetyl-CoA carboxylase
reaction produces malonyl-CoA
for fatty acid synthesis
(b) A mechanism for the acetyl-CoA

carboxylase reaction:
Step 1: Bicarbonate activated for
carboxylation reactions by formation
of N-carboxybiotin.
ATP drives the reaction forward,
with transient formation of a
carbonyl-phosphate intermediate.
Step 2: In a typical biotin-dependent
reaction, nucleophilic attack by the
acetyl-CoA carbanion on the
carboxyl carbon of N-carboxybiotin
—a transcarboxylation—yields the
carboxylated product, malonyl-
CoA Malonyl-CoA
Stage 3: Repetitive addition and reduction of two carbon units
Fig. 21.17 - Pathway of Palmitate Synthesis from Acetyl-CoA and Malonyl-CoA
• Addition of two-carbon units to

growing fatty acid chain is catalyzed
by giant enzyme complex called
fatty acid synthase which is made
up of individual enzymes
• Acetyl group from Acetyl-CoA is transferred
to ACP
• ACP = Acyl Carrier Protein, part of fatty
acid synthase complex
• Acetyl group is bound to ACP as a
thioester
• Usual product of fatty acid

synthesis is palmitate, 16-carbon
saturated fatty acid 
Table 21.2 - Comparison of Fatty Acid Degradation
and Biosynthesis

Figure 21.20 - Portion of an Animal Cell, Showing the
Sites of Various Aspects of Fatty Acid Metabolism
• Cytosol is site of fatty acid anabolism, of

formation of acyl-CoA
• Acyl-CoA is transported to mitochondrion for
catabolism by β-oxidation process
• Some chain-lengthening reactions (beyond
C16) take place in mitochondria. Fatty acid
synthase cannot generate fatty acids longer
than C16 palmitate
• Other chain-lengthening reactions and
reactions that introduce double bonds take
place in ER see next slide 
Figure 21.20 - Portion of an Animal Cell, Showing the
Sites of Various Aspects of Fatty Acid Metabolism

• Enzymes bound to endoplasmic reticulum introduce
double bonds into saturated fatty acids
• Ex:

Essential Fatty Acids
• Mammals lack the enzymes that introduce double bonds
beyond carbon 9
• Polyunsaturated fatty acids with double bonds beyond carbon
9 are essential and must be obtained from diet
Linolenate (omega-3
fatty acid)
in flax seeds, fish oil
Linoleate (omega-6
fatty acid)
In vegetable oils,
nuts, seeds
Quick Quiz:
Why do fatty acid synthesis and

breakdown not compete with
each other in the body?


Quick Quiz:
Why do fatty acid synthesis and

breakdown not compete with each other
in the body?
• Synthesis and breakdown take place

in two separate compartments of the
cell
• One process uses NADH/NAD+ and
the other uses NADPH/NADP+
• They are not attached to the same
carrier molecule in the two processes


8. Cholesterol
Biosynthesis
• Liver - Principal site of cholesterol synthesis in mammals

• Smooth ER – Important site for cholesterol synthesis and
conversion of cholesterol into other steroids

Cholesterol Biosynthesis
• All carbon atoms of cholesterol and steroids
synthesized from cholesterol are derived from the
two-carbon acetyl group of acetyl-CoA
• Cholesterol: Steroid that occurs in cell membranes
and is the precursor of other steroids
• Cholesterol biosynthesis involves many reaction
steps
• Involvement of isoprene units is key to biosynthesis
of steroids
• Isoprene units: Five-carbon groups that are used in
biosynthesis of steroids
Figure 21.27 - Outline of the Biosynthesis
of Cholesterol
6 carbons
Multiple
steps Decarboxyl-
Isoprene unit
ation
Condensation of
three acetyl Six isoprene units
groups produces condense to form
mevalonate Squalene (30
carbons)
Cholesterol (27
carbons)

Cholesterol Biosynthesis (continued 1)
• Synthesis begins with
condensation of two
molecules of acetyl-CoA
• Third molecule of acetyl-
CoA condenses with
acetoacetyl-CoA to produce
β-hydroxy-β-methylglutaryl-
Control
CoA (HMG-CoA) point in
• Formation of mevalonate is cholesterol
biosynthesis
completed by reduction of
thioester that gives a 1° mevalonate
alcohol
• Drugs such as lovastatin are inhibitors of
hydroxymethyl-CoA reductase (HMG-CoA
reductase) and are widely prescribed to lower blood
cholesterol levels

• Isopentenyl pyrophosphate is produced after:
• Phosphorylation of the 1° alcohol of mevalonate (two
moles of ATP) followed by phosphorylation of the 3°
alcohol (one mole of ATP)
• Concerted decarboxylation and β-elimination of
phosphate ion
• Enzyme-catalyzed isomerization of the carbon-
carbon double bond gives dimethylallyl
pyrophosphate

• Dimethylallyl pyrophosphate is converted to
isopentenyl pyrophosphate, which is followed by H +
loss to give farnesyl pyrophosphate
• Two molecules of farnesyl pyrophosphate (C15)
condense to form squalene (C30)

Figure 21.30 - Structures of Lovastatin and Synvinolin, Mevinolinic acid, and
the Tetrahedral Intermediate in the HMG-CoA Reductase Mechanism
Metabolized
Transition-state analogue to

Figure 21.31 - Conversion of Mevalonate to
Squalene
15 C
30 C
Figure 21.32 - Cholesterol is Synthesized
from Squalene via Lanosterol

Figure 21.33 - Synthesis of Bile Acids from
Cholesterol
Bile acids - Cholate,

Glycocholate
• Emulsify lipid
droplets; aid in
digestion

Cholesterol as a Precursor to Steroids
• Sex hormones
• Pregnenolone - Formed
from cholesterol and
produces
progesterone, precursor
Sex hormones
for: testosterone
estradiol
cortisone (example of
glucocorticoids
aldosterone (example of
mineralocorticoids)

Role of Cholesterol in Heart Disease
• Cholesterol must be packaged for transport in the
bloodstream
• Several classes of lipoproteins are involved in the
transport of lipids in blood
• Low-density lipoproteins (LDLs): Transports
cholesterol from liver to rest of the body
• High-density lipoproteins (HDLs): Transports
cholesterol back to liver for degradation to bile acids

Role of Cholesterol in Heart Disease
(continued)
• High levels of LDL and

low levels of HDL are
correlated with
development of heart
disease
• Regular strenuous
exercise increases HDL
levels and decreases
probability of heart
disease
• Smoking reduces level of
HDL and is highly
correlated with heart
disease
Figure 21.36 - Fate of Cholesterol in the Cell

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Chapter 21

© 2018 Cengage Learning. All Rights Reserved.

© 2018 Cengage Learning. All Rights Reserved.

(21-8) Cholesterol biosynthesis

© 2018 Cengage Learning. All Rights Reserved.

© 2018 Cengage Learning. All Rights Reserved.

© 2018 Cengage Learning. All Rights Reserved.

• Hydrophobic nature of fatty acids allows close packing in

© 2018 Cengage Learning. All Rights Reserved.

• Many mammals, such as this

Fatty acid degradation is a key energy source

• Adipose tissue is located throughout the

1. Degradation of TAG to release fatty acids and

2. Activation of the fatty acids and transport into the

3. Degradation of the fatty acids to acetyl CoA for

© 2018 Cengage Learning. All Rights Reserved.

© 2018 Cengage Learning. All Rights Reserved.

© 2018 Cengage Learning. All Rights Reserved.

© 2018 Cengage Learning. All Rights Reserved.

Hormone binds to receptor on

Hormone binding activates adenylate

Protein kinase phosphorylates

Main hormone that has this effect is

• Reaction rendered irreversible by action of pyrophosphatase

© 2018 Cengage Learning. All Rights Reserved.

Derived from Vitamin B5

© 2018 Cengage Learning. All Rights Reserved.

© 2018 Cengage Learning. All Rights Reserved.

© 2018 Cengage Learning. All Rights Reserved.

© 2018 Cengage Learning. All Rights Reserved.

© 2018 Cengage Learning. All Rights Reserved.

© 2018 Cengage Learning. All Rights Reserved.

Δ symbol represents a double bond,

© 2018 Cengage Learning. All Rights Reserved.

© 2018 Cengage Learning. All Rights Reserved.

© 2018 Cengage Learning. All Rights Reserved.

• Nine moles of acetyl-CoA produced from each mole

• FADH2 and NADH produced by b-oxidation and

© 2018 Cengage Learning. All Rights Reserved.

© 2018 Cengage Learning. All Rights Reserved.

© 2018 Cengage Learning. All Rights Reserved.

• Three cycles of β-oxidation on linoleoyl-

© 2018 Cengage Learning. All Rights Reserved.

© 2018 Cengage Learning. All Rights Reserved.

can be used as a fuel in

© 2018 Cengage Learning. All Rights Reserved.

© 2018 Cengage Learning. All Rights Reserved.

Citrate + CoA - SH + ATP  Acetyl - CoA + Oxaloacetate + ADP + Pi

© 2018 Cengage Learning. All Rights Reserved.

• Net effect of these two reactions is replacement of

© 2018 Cengage Learning. All Rights Reserved.

Citrate that is exported

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© 2018 Cengage Learning. All Rights Reserved.

(b) A mechanism for the acetyl-CoA

• Addition of two-carbon units to

• Usual product of fatty acid

© 2018 Cengage Learning. All Rights Reserved.

• Cytosol is site of fatty acid anabolism, of

© 2018 Cengage Learning. All Rights Reserved.

© 2018 Cengage Learning. All Rights Reserved.

Why do fatty acid synthesis and

© 2018 Cengage Learning. All Rights Reserved.