Chapter 21

Lipid Metabolism

Paul D. Adams • University of Arkansas

cengage.com/chemistry/campbell
Chapter Outline

20-1 Lipids Are Involved in the Generation and Storage of Energy

20-2 Catabolism of Lipids

21-3 The Energy Yield from the Oxidation of Fatty Acids

21-4 Catabolism of Unsaturated Fatty Acids and Odd-Carbon Fatty Acids

21-5 Ketone Bodies

21-6 Fatty-Acid Biosynthesis

21-7 Cholesterol Biosynthesis

Lipids are Involved in Generation and
Storage of Energy
• The oxidation of fatty acids (FA) in triacylglycerols are the
principal storage form of energy for most organisms
• Their carbon chains are in a highly reduced form
• The energy yield per gram of fatty acid oxidized is greater
than that per gram of carbohydrate oxidized
Catabolism of Lipids
• Lipases catalyze
hydrolysis of bonds
between fatty acid and
the rest of
triacylglycerols
• Phospholipases
catalyze hydrolysis of
bonds between fatty
acid and the rest of
phosphoacylglycerols
• May have multiple sites
of action
The Liberation of Fatty Acids from Triacylglycerols
Liberation of fatty acids from triacylglycerols in adipose tissue is hormone dependent

Epinephrine
Fatty Acid Activation
• Fatty acid oxidation begins with activation
• A thioester bond is formed between the carboxyl
group of the FA and the thiol of CoA-SH

The esterification takes place in the cytosol but the rest of F.A oxidation takes place in mitochondrial matrix
The Role of Carnitine in Acyl-CoA Transfer
• The acyl-CoA crosses the outer mitochondrial
membrane, but not the inner membrane
• The acyl group is then transferred to carnitine, carried
across the inner mitochondrial membrane, and
transferred to mitochondrial CoA-SH
• Carnitine Palmitoyltransferase (CPT-1) has
specificity for acyl groups between 14 and 18
carbons long
 transesterification

Carnitine translocase Carnitine palmitoyltransferase (CPT-I)

Carnitine palmitoyltransferase (CPT-II)

-Oxidation
• -Oxidation: a series of reactions that cleaves
carbon atoms two at a time from the carboxyl end of
a fatty acid
• The complete cycle of one -oxidation requires four
enzymes
• Reaction 1: Oxidation of the , carbon-carbon single
bond to a carbon-carbon double bond
• Reaction 2: Hydration of the carbon-carbon double
bond
• Reaction 3: Oxidation of the -hydroxyl group to a
carbonyl group
• Reaction 4: Cleavage of the carbon chain by a
reverse Claisen reaction
 -Oxidation (Cont’d)
The -oxidation of saturated fatty acids involves a
cycle of four enzyme-catalyzed reactions
b-Oxidation Gives Rise to Nine 2-Carbon
Units

Peroxisomes and glyoxysomes, organelles that carry out oxidation,

are also sites of β-oxidation in addition to the mitochondrial matrix
Summary
• Fatty acids are activated and transported to the
mitochondrial matrix for further catabolism

• The breakdown of fatty acids takes place in the

mitochondrial matrix and proceeds by successive
removal of two-carbon units as acetyl-CoA

• Each Cleavage of a two-carbon moiety requires a

four-step reaction sequences called -oxidation
The Energy Yield from Oxidation of Fatty
Acids
• The energy released by the oxidation of acetyl-CoA
formed by -oxidation of FA can be used to produce
ATP
• Eight cycles of -oxidation are required for the
oxidation of Stearic acid to acetyl-CoA
Energy Yield from FA Oxidation (Cont’d)
• The overall equation for oxidation of stearic acid
can be obtained by adding the equations for b-
oxidation, the citric acid cycle, and oxidative
phosphorylation
Energy Yield from FA Oxidation (Cont’d)
Summary
• The complete oxidation of FA by the citric acid cycle
and the electron transport chain releases large
amounts of energy

• When we include the reoxidation of NADH and

FADH2 from -oxidation and the citric acid cycle, we
obtain a net yield of 120 ATP for a single molecule of
stearic acid
Metabolic water
• Common feature of aerobic metabolism
• Water is produced in the oxidation of fatty acids

Kangaroo rat
Catabolism of Unsaturated FA and Odd-
Numbered FA
• Odd-numbered FA are
not frequently
encountered, but do
also undergo -
oxidation

• The last -oxidation

cycle of a fatty acid
with an odd number of
carbons gives
propionyl-CoA
Oxidation of an Unsaturated FA
• A cis-trans isomerization is needed to convert
unsaturated FA to acetyl-CoA

• This enzyme is known as an isomerase

• Oxidation of unsaturated FA does not generate as

much ATP relative to saturated FA with the same # of
carbons
b-Oxidation of Unsaturated FA
Summary
• FA with odd number of carbons produce propionyl-
CoA in the last step of the oxidation

• Propionyl-CoA can be converted to succinyl-CoA,

which plays a role in the citric acid cycle

• The oxidation of unsaturated FA requires enzymes

that catalyze isomerization around the double bonds
so that oxidation can proceed
Ketone Bodies
• Formation of ketone bodies occurs when the amount
of acetyl-CoA produced is excessive compared to the
amount of oxaloacetate available to react with it
• Intake high in lipids and low in carbohydrates
• Diabetes not suitably controlled
• Starvation
• Ketone bodies are: acetone, -hydroxybutyrate, and
acetoacetate
• Formed principally in liver mitochondria
• Can be used as a fuel in most tissues and organs
Ketone Bodies (Cont’d)

• If an organism has an
excess of acetyl-CoA, it
produces ketone bodies.

• This situation can arise

from an excessive intake of
fats compared to
carbohydrates, or from
diabetes.

• Starvation (lipid is used

for energy) and diabetes
(inability to metabolize
• The excess of acetoacetate and consequently
acetone, is a pathological condition known as ketosis
• The body deals with the consequent lowering of blood
pH (ketoacidosis) by excreting H+ into the urine,
accompanied by excretion of Na+, K+ and water
• Ketone bodies are synthesized mainly in liver
mitochondria but they are not used there due to the
lack of enzymes to recover acetyl-CoA.
• Instead, they are transported in the bloodstream
(water-soluble) without a carrier protein.
• In heart muscle and renal cortex, acetoacetate is the
preferred source of energy.
• Starvation condition in brain can lead to the use of
acetoacetate for energy.
Fatty Acid Biosynthesis
• Biosynthesis is not exact
reversal of oxidation
• Biosynthetic reactions
occur in the cytosol
• First step: transport of
acetyl-CoA from
mitochondrial matrix to
cytosol
• β-oxidation of fatty acids
or decarboxylation of
pyruvate
• Transport based on the
fact that citrate can
cross the mitochondrial
membrane
Fatty Acid Biosynthesis (Cont’d)
• Carboxylation of acetyl-CoA occurs in the cytosol
• Catalyzed by acetyl-CoA carboxylase
• Biotin is the carrier of the carboxyl group
• Malonyl-CoA is key intermediate that is produced
The Acetyl-CoA Carboxylase Reaction
• Biotin is an important cofactor in this reaction as well

Malonyl-CoA
Biosynthesis of Palmitate from Acetyl- and
Malonyl-CoA
ACP: acyl carrier protein
HS-Ksase: β-ketoacyl-S-ACP-synthase
What is the mode of action of fatty-acid synthase?
• 2 of the 3 C-atoms of the malonyl group of
malonyl-CoA are added to the growing fatty acid
chain with each cycle of the synthesis
• Requires a multi-enzyme complex located in the
cytosol called fatty acid synthase
• Usual product of fatty-acid anabolism is
palmitate, the 16-C saturated fatty acid (all
come from acetyl-CoA)
• Priming step in which one molecule of acetyl-CoA
is required for each molecule of palmitate
produced
• Double bond addition takes place in the ER
• Catalyzed by a mixed function oxidase that requires
NAD(P)H and O2
• Mammals cannot introduce a double bond beyond C9
as a result linoleate (2 double bonds) and linolenate
(3 double bonds) must be included in the diet →
essential fatty acids (precursors of prostaglandins)
Summary
• Acetyl-CoA is transported to the cytosol and converted to
malonyl-CoA
• The biosynthesis of FA proceeds by the addition of 2-carbon
units to the hydrocarbon chain. The process is catalyzed by
the fatty-acid synthase complex

Comparison of FA Degradation and

Biosynthesis
Sites of Fatty Acid Metabolism in an Animal Cell
Cholesterol Biosynthesis
• All carbon atoms of cholesterol and steroids
synthesized from it are derived from the two-carbon
acetyl group of acetyl-CoA

• Involves many reaction steps

• Involvement of isoprene units are key to the

biosynthesis of steroids and other biomolecules
known as terpenes
Outline of Cholesterol Biosynthesis
Condensation of 3 acetyl-CoA

decarboxylation

Key point in the synthesis of steroids

and terpenes which form vit A, E, and K
Also involved in CoQ synthesis, tRNA
and Derivatives of proteins

6 isoprene condense to form squalene

A 30 C compound which is converted to
Cholesterol (27 C)
• Acetate →Mevalonate → [Isoprene] → squalene → cholesterol
C2 C6 C5 C30 C27

• 12 of the carbon atoms of cholesterol arise from the carboxyl

carbon of the acetyl group (labeled c) and 15 carbons arise
from the methyl carbon (labeled m)
Cholesterol as a Precursor
• Cholesterol is the precursor
for a number of steroid
hormones
The Synthesis of Steroid Hormones from
Cholesterol

Carbohydrate metabolism

Electrolyte (minerals ) and water metabolism

Role of Cholesterol in Heart Disease
• Lipids are transported in the blood stream by
lipoproteins
• Cholesterol and its fatty acid esters are packaged
into several classes of lipoproteins for transport
The LDL Particle
The Fate of Cholesterol
The Fate of Cholesterol

• Dietary cholesterol suppresses the synthesis of

cholesterol by the body, especially in tissues other
than the liver.

• Free cholesterol also, inhibit synthesis of LDL

receptors. As a result, cellular uptake of cholesterol is
inhibited and the level of LDL in the blood increases,
leading to deposition of atherosclerotic plaques.
Summary
• The biosynthesis of cholesterol proceeds by the
condensation of five-carbon isoprenoid units

• Isoprenoid units in turn are derived from the reaction

of three acetyl-CoA units

• Once cholesterol is formed, it serves as a precursor

for other steroids

• Cholesterol must be packaged for transport in the

bloodstream. Some of these forms of cholesterol play
a role in heart disease