Chapter 25

Lipid Metabolism
 Chapter 25
Table of Contents
25.1 Digestion and Absorption of Lipids
25.2 Triacylglycerol Storage and Mobilization
25.3 Glycerol Metabolism
25.4 Oxidation of Fatty Acids
25.5 ATP Production from Fatty Acid Oxidation
25.6 Ketone Bodies
25.7 Biosynthesis of Fatty Acids: Lipogenesis
25.8 Relationship Between Lipogenesis and Citric Acid Cycle
Intermediates
25.9 Biosynthesis of Cholesterol
25.10 Relationships Between Lipid and Carbohydrate Metabolism

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 Section 25.1
Digestion and Absorption of Lipids

• Dietary Lipids: 98% triacylglycerols (TAGs):

– Fats and oils
• Salivary enzymes (water soluble) in the mouth have no
effect on lipids (TAGs) which are water insoluble
• In Stomach: Most, not all, of TAGs change physically to
small globules or droplets -- called chyme which floats
above other material:
– It is a physical not chemical process -- enters into
small intestine

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 Section 25.1
Digestion and Absorption of Lipids

• Lipid digestion starts in the stomach:

– Gastric lipase hydrolyzes ester bonds -- 2 fatty acids
and one monoacylglycerol --About 10% of TAGS are
hydrolyzed
• High fat foods stay in stomach for longer time -- high fat meal
gives you a feeling of being full for longer time

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 Section 25.1
Digestion and Absorption of Lipids

• Chyme enters into small intestine and is emulsified

(stabilization of colloidal suspension) with bile salts
• Pancreatic lipase hydrolyzes ester bonds of fatty acids
and glycerol
– Normally 2 out of 3 fatty acids are hydrolyzed
• Fatty acids, monoacyglycerols and bile salts make small
droplets: called micelles -- hydrophobic chain in the
interior
• Micelles consist of monoacyglycerols and free fatty
acids:
– Small enough to absorb through intestinal cells

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 Section 25.1
Digestion and Absorption of Lipids

• In the intestinal cells monoacylglycerols and free fatty acids are

repackaged to from TAGs
• These new TAGs combine with membrane lipids (phospholipids and
cholesterol) and lipoproteins to form chylomicron
• Chylomicrons transport TAGs from intestinal cells to the
bloodstream
– This is accomplished though the lymphatic system
• In the bloodstream TAGs are completely hydrolyzed by lipase
enzymes
• Fatty acids and glycerol are absorbed by the cell and are either
broken down to the acetyl Co-A for energy or repacked to store as
lipids

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 Section 25.2
Triacylglycerol Storage and Mobilization

• Most cells have limited capability of TAGs storage

• TAGs stored in specialized cells called adipocytes found
in adipose tissue:
– Largest cells in the body -- cytoplasm converted to TAG’s
droplet
– Located primarily beneath the skin especially in abdominal
region and vital organs
– Adipose tissue also serve as a protection against the heat loss
and mechanical shock

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 Section 25.2
Triacylglycerol Storage and Mobilization

• Several hormones trigger the hydrolysis of TAGs via

activation of cAMP (activate hormone sensitive lipase;
HSL) and release of glycerol and fatty acids into the
bloodstream -- called triacylglycerol mobilization
• ~10% of TAGs replaced everyday
• Triacylglycerol energy reserves (fat reserves) are the
human body’s major source of stored energy:
– Energy reserves associated with protein, glycogen,
and glucose are small to very small when compared
to fat reserves

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 Section 25.3
Glycerol Metabolism

• Taken to liver or kidney by blood -- converted to

dihydroxyacetone phosphate in two steps:
– Phosphorylation of primary hydroxyl group of the
glycerol
– Secondary alcohol group of glycerol is oxidized to
ketone

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 Section 25.4
Oxidation of Fatty Acids

• There are three parts to the process by which fatty acids

are broken down to obtain energy.
• Activated by binding to Coenzyme-A - product called
acyl Co-A.
• Transported to mitochondrial matrix
• Repeatedly (fatty acid spiral) oxidized to produce acetyl
Co-A, FADH2 and NADH
• note acyl has longer R group but acetyl has CH3
attached to C=O

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 Section 25.4
Oxidation of Fatty Acids

Fatty Acid Activation

• Takes place in outer mitochondrial membrane
• FA reacts with coenzyme A in the presence of ATP to
produce high energy acyl CoA
• ATP is converted to AMP

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 Section 25.4
Oxidation of Fatty Acids

Fatty Acid Transport

• A shuttle mechanism is involved in the transport of acyl
CoA from mitochondrial membrane to mitochondrial
matrix

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 Section 25.4
Oxidation of Fatty Acids

Reactions of the Beta-Oxidation Pathway

• Four reactions repeatedly cleaves two-carbon units from
the carboxyl end of saturated fatty acids
– Also called b-oxidation spiral because the second or
beta carbon from carboxyl end of the chain oxidized
• This process removes two carbon units and converts to
acetyl CoA with FADH2 and NADH being produced

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 Section 25.4
Oxidation of Fatty Acids

Four Steps of the Beta-Oxidation Pathway

• Step 1: Oxidation (dehydrogenation):
– Hydrogen atoms are removed from the a and b
carbons, creating a double bond between these two
carbon atoms.
– FAD is the oxidizing agent, and a FADH2 molecule is
a product.

• Step 2: Hydration:
– A molecule of water is added across the trans double
bond, producing a secondary alcohol at the b-carbon
position
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 Section 25.4
Oxidation of Fatty Acids

Four Steps of the Beta-Oxidation Pathway

• Step 3: Oxidation (dehydrogenation):
– The b-hydroxy group is oxidized to a ketone
functional group with NAD+ serving as the oxidizing
agent.

• Step 4: Chain Cleavage:

– The fatty acid chain is broken between the a and b
carbons by reaction with a coenzyme A molecule.
– The result is an acetyl CoA molecule and a new acyl
CoA molecule that is shorter by two carbon atoms
than its predecessor.
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 Section 25.4
Oxidation of Fatty Acids

Unsaturated Fatty Acids

• Oxidation of unsaturated FAs require two additional
steps compared to saturates FAs
• Epimerase: changes D-configuration to an L
configuration
• Cis-trans isomerase: trans-(2,3) double bond is formed
from cis-(3,4) double bond

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 Section 25.5
ATP Production From Fatty Acid Oxidation

Fatty Acid vs. Glucose Oxidation: A Comparison

• Spiral fatty acid oxidation (previous slide) produce net 120 ATP
molecules by oxidation of 18 carbon atom fatty acid (stearic acid)
• Note that 2 ATP molecules are needed for activation of fatty acids so
net ATP production is 120 molecules
• 1 Glucose molecule (6 carbon atoms) produces 30 ATP molecules
• Three molecules of glucose (18 Carbon atoms) produce 90 ATP
• 1 Stearic acid molecule (18 carbon atoms) produces 122 molecules
of ATP 10 ATP
9 Acetyl CoA x = 90 ATP
1 Acetyl CoA
1.5 ATP
8 FADH2 x = 12 ATP
1 FADH2
2.5 ATP
8 NADH x = 20ATP
1 NADH
Total = 122 ATP Return to TOC

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 Section 25.5
ATP Production From Fatty Acid Oxidation

Fatty Acid vs. Glucose Oxidation: A Comparison

• Stoichiometric Comparison:
– 1.00 g Stearic acid produces = 0.423 mole ATP
– 1.00 g glucose produces 0.167 mole ATP
• Stearic acid produces 2.5 time more energy than glucose

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 Section 25.6
Ketone Bodies

• Acetyl CoA formed from fatty acid spiral further

processed by Citric Acid Cycle (Krebs Cycle) – Therefore
an adequate balance in carbohydrate and lipid
metabolism required
• Lipid-Carbohydrate Metabolism disturbed by:
– Dietary intakes high in fat and low in carbohydrates
– Diabetic conditions -- glucose not used properly
– Prolonged fasting conditions

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 Section 25.6
Ketone Bodies

• Under low supply of oxaloacetate the acetyl CoA will be

in excess (increased concentration)
• As a consequence the excess acetyl CoA is converted to
ketone bodies

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 Section 25.6
Ketone Bodies

Ketogenesis
• Ketogenesis involves the production of ketone bodies
from acetyl CoA
• Synthesis of ketone bodies from acetyl CoA primarily in
liver mitochondria -- diffused into blood stream and
transported to peripheral tissues

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 Section 25.6
Ketone Bodies

Ketogenesis
• Step 1: First Condensation of two acetyl CoA molecules
to produce acetoacetyl CoA, a reversal of the last step of
the Beta-oxidation pathway
• Step 2: Second Condensation: Acetoacetyl CoA then
reacts with a third acetyl CoA and water to produce 3-
hydroxy-3-methylglutaryl CoA (HMG-CoA) and CoA-SH.
• Step 3: Chain cleavage: HMG-CoA is cleaved to acetyl
CoA and acetoacetate.
• Step 4: Reduction: Acetoacetate is reduced to Beta-
hydroxybutyrate.

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 Section 25.6
Ketone Bodies

Summary of Ketogenesis

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 Section 25.7
Biosynthesis of Fatty Acids: Lipogenesis

Lipogenesis vs. Fatty Acid Degradation

Lipogenesis Degradation of a fatty acids

Takes place in cell cytosol Takes place in
mitochondrial matrix
A multi-enzyme complex Enzymes are not complexed
called fatty acid synthase and the steps are
catalyzes reactions independent
Intermediates bonded to The carrier for fatty acid
acyl carrier protein (ACP) spiral is CoA
Depends upon reducing Dependent upon FAD and
agent NADPH NAD+
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 Section 25.7
Biosynthesis of Fatty Acids: Lipogenesis

The Citrate–Malate Shuttle System

• Acetyl CoA is the
starting material for
lipogenesis.
• Acetyl CoA needed for
lipogenesis is
generated in
mitochondria therefore
it must first be
transported to the
cytosol.
• Citrate-malate transport
system helps transport
acetyl CoA to cytosol
indirectly.
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 Section 25.7
Biosynthesis of Fatty Acids: Lipogenesis

ACP Complex Formation

• ACP Complex Formation:
– All intermediates in fatty acid synthesis are linked to
carrier proteins (ACP-SH)
– ACP-SH can be regarded as a “giant CoA-SH
molecule”

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 Section 25.7
Biosynthesis of Fatty Acids: Lipogenesis

Chain Elongation
• Four reactions constitute first step of chain elongation
process
– Condensation: Acetyl-ACP and malonyl-ACP
condense together to form acetoacetyl-ACP
– Hydrogenation: The keto group of the acetoacetyl
complex is reduced to alcohol by NADPH
– Dehydration: Water is removed from alcohol to form
an alkene
– Hydrogenation: Hydrogen is added to alkene 3 to
form saturated butyryl ACP from NADPH

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 Section 25.7
Biosynthesis of Fatty Acids: Lipogenesis

Unsaturated Fatty Acid Biosynthesis

• To produce a double bond oxygen is needed and water
is removed
• In humans and animals, enzymes can only introduce
double bond between C-4 and C-5 and between C-9 and
C-10
• Consequence: Important essential unsaturated fatty
acids linoleic (18 carbons with C-9 and C-12 double
bond and linolenic acid (18 carbon with C-9, C-12 and C-
15 double bonds can’t be synthesized - should come
from diet - plants have enzymes to synthesize them

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 Section 25.8
Relationships Between Lipogenesis and Citric Acid Cycle Intermediates

• The last four intermediates of the citric acid cycle bear

the following relationship to each other.
• Saturated C4 diacid  Unsaturated C4 diacid  hydroxy
C4 diacid  keto C4 diacid.
• The intermediate C4 carbon chains of lipogenesis bear
the following relationship to each other.
• Keto C4 monoacid  hydroxy C4 monoacid 
unsaturated C4 monoacid  saturated C4 monoacid.

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 Section 25.8
Relationships Between Lipogenesis and Citric Acid Cycle Intermediates

• Two important contrasts between citric acid cycle

intermediates and Lipogenesis intermediates:
– The citric acid intermediates involve C4 diacids and
the lipogenesis intermediates involve C4 monoacids
– The order in which the various acid derivative types
are encountered in lipogenesis is the reverse of the
order in which they are encountered in the citric acid
cycle.

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 Section 25.9
Biosynthesis of Cholesterol

Cholesterol
• Secondary component of cell membrane
• Precursor for bile salts, sex hormones and adrenal
hormone
• Body synthesizes 1.5 - 2.0 g of cholesterol everyday
from acetyl CoA units
– Average daily dietary intake is ~ 0.3 g
• Synthesis of cholesterol occur in liver
• Synthesis requires at least 15 acetyl CoAs and involves
~27 separate enzymetic steps

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 Section 25.9
Biosynthesis of Cholesterol
An Overview of the Biosynthetic Pathway for Cholesterol
Synthesis

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 Section 25.9
Biosynthesis of Cholesterol

Biosynthetic Relationships Among Steroid Hormones

• Once cholesterol is synthesized, it is converted to
five major classes of steroid hormones: progestins,
androgens, estrogens and vitamin D

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 Section 25.10
Relationships Between Lipid and Carbohydrate Metabolism

• Acetyl Co-A is the primary link between these two

metabolic pathways
– Acetyl Co-A is the starting material for the
biosynthesis of fatty acids, cholesterol and ketone
bodies
– Acetyl CoA is the product for glucose, glycerol and
fatty acids

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 Section 25.10
Relationships Between Lipid and Carbohydrate Metabolism

Four Possible Fates of Acetyl CoA

• Oxidation in the citric acid cycle: both lipids and
carbohydrates supply acetyl CoA
• Ketone body formation: Very important when imbalance
between carbohydrate and lipid metabolism
• Fatty acid biosynthesis: the buildup of excess acetyl CoA
when dietary intake exceeds energy needs energy
needs leads to accelerated fatty acid biosynthesis
• Cholesterol biosynthesis: It occurs when the body is in
an acetyl CoA- rich state

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