Chapter 25

Lipid Metabolism

Chapter 25

Table of Contents
25.1Digestion and Absorption of Lipids
25.2Triacylglycerol 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 Fate of Fatty-Acid Generated Acetyl CoA
25.10 Relationships Between Lipid and Carbohydrate Metabolism
25.11B Vitamins and Lipid 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:

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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

Chyme enters into small intestine and is emulsified with bile salts
Pancreatic lipase hydrolyzes ester bonds to form 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 form TAGs
These new TAGs combine with membrane lipids (phospholipids and
cholesterol) and lipoproteins to form chylomicrons
Chylomicrons transport TAGs from intestinal cells to the
bloodstream though the lymphatic system
From the lymphatics the fats flow through the thoracic duct into the
bloodstream and then to the liver
In the liver some of the fats are changed to phospholipids, so the
blood leaving the liver contains both fats and phospholipids
These phospholipids, such as sphingomyelin and lecithin are
necessary for the formation of nerve and brain tissues
Lecithins are also involved in the transport of fat to the tissues
Cephalin, another phospholipid, is involved in the normal blood
clotting
From the liver, some fat goes to the cells through the bloodstream

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Section 25.1

Digestion and Absorption of Lipids

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
The fat in excess of what the cells need is stored in specialized cells
called adipocytes (the largest cell in the body) in the adipose tissue
Located primarily beneath the skin especially in abdominal region and
vital organs
Adipose tissue also serves as a protection against the heat loss and
mechanical shock

Triacylglycerol energy reserves (fat reserves) are the human bodys

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
Recall that DHAP is part of the glycolysis pathway
This compound may be converted to lactic acid or to glycogen in the liver or
muscle tissue or to pyruvic acid, which enters the TCA cycle
Thus, the glycerol part of a fat is metabolized through the carbohydrate
sequence

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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.
1. Activation of the fatty acid by binding to Coenzyme-A product is called acyl Co-A
2. Transport of acyl Co-A to mitochondrial matrix
3. Repeated oxidation (fatty acid spiral) to produce acetyl Co-A,
FADH2 and NADH

Note: the difference between the designations acyl CoA and

acetyl CoA is that acyl refers to a random-length fatty acid
carbon chain that is covalently bonded to coenzyme A,
whereas acetyl refers to a two-carbon chain covalently
bonded to coenzyme A.

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Section 25.4

Oxidation of Fatty Acids

Fatty Acid Activation and Transport

Activation of fatty acid takes place

in outer mitochondrial membrane
FA reacts with coenzyme A at the
expense of 2 moles ATP to
produce high energy acyl CoA
acyl CoA is too large to pass
through the inner mitochondrial
membrane to the mitochondrial
matrix, where the enzymes
needed for fatty acid oxidation are
located; it is converted to acyl
carnitine
a shuttle mechanism involving the
molecule carnitine effects the
transport of acyl CoA into the
mitochondrial matrix.

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Section 25.4

Oxidation of Fatty Acids

Reactions of the Beta-Oxidation Pathway

Repeated oxidation of fatty acid, cycling through a series of four reactions to

produce acetyl CoA, FADH2, and NADH.

the oxidation of fatty acids follow the -oxidation theory that involves the
oxidation of the 2nd carbon atom from the acid end of the saturated fatty acid
molecule, the -carbon atom.
in this process, -oxidation removes two carbon atoms at a time from the
fatty acid chain; i.e., an 18-carbon fatty acid is oxidized to a 16-carbon fatty
acid, then to 14-carbon fatty acid, and so on until the oxidation process is
complete
the process is also known as fatty acid spiral because the fatty acid goes
through the cycle again and again until it is finally degraded to acetyl CoA.
the fatty acid spiral is a repetitive series of four reactions
(dehydrogenation, hydration, dehydrogenation, release of acetyl CoA)
in which each sequence produces acetyl CoA, FADH2, NADH, and an acyl
CoA that is shorter than the previous acyl CoA by two carbon atoms.

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Section 25.4

Oxidation of Fatty Acids

Four Steps of the Beta-Oxidation
Pathway

Step 1: Oxidation (dehydrogenation):

Step 2: Hydration:

A molecule of water is added across the

trans double bond, producing a
secondary alcohol at the beta-carbon
position

Step 3: Oxidation (dehydrogenation):

FAD is the oxidizing agent, and a FADH2

molecule is a product.

The beta-hydroxyl group is oxidized to a

keto functional group with NAD+ serving
as the oxidizing agent.

Step 4: Chain Cleavage:

The fatty acid chain is broken between

the alpha and beta 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

p925

Section 25.4

Oxidation of Fatty Acids

The acetyl CoA produced enters the citric acid cycle and the new
molecule of active fatty acid (active acyl CoA) goes through the same
sequence again, each time losing two carbon atoms until the entire
molecule has been oxidized
The sequence presupposes the presence of fatty acids containing an
even number of carbon atoms, a condition usually encountered in
nature
If fatty acid containing odd number of carbon atoms are oxidized they
follow the same steps except that the final products are acetyl CoA
and propionyl CoA. The propionyl CoA is changed in a series of steps
to succinyl CoA, which enters the citric acid cycle, as does the acetyl
CoA; these reactions require the presence of cobamide and biotin
The unsaturated fatty acids are metabolized slowly; they must first be
reduced by some of the dehydrogenases found in the cells, then they
can follow the fatty acid spiral for oxidation
The FADH2 and the NADH + H+ enter the respiratory chain

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Section 25.5

ATP Production From Fatty Acid Oxidation

Fatty Acid vs. Glucose Oxidation: A Comparison

the oxidation of 1 g of fat produces

more than twice as much energy
as the oxidation of 1 g of
carbohydrate
-oxidation of 18:0 fatty acid
(stearic acid) produces a net of 120
ATP molecules
2 ATP molecules are needed for
activation of fatty acids so net ATP
produced is 120 molecules
1 Glucose molecule (6 carbon
atoms) produces 30 ATP molecules
Three molecules of glucose (18
Carbon atoms) produce 90 ATP
Stearic acid produces 2.5 time
more energy than glucose
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Section 25.6

Ketone Bodies

Ordinarily, most of the acetyl CoA produced from the fatty acid spiral is
further processed through the Krebs cycle.
Therefore an adequate balance in carbohydrate and lipid metabolism is
required
The first step of the Krebs cycle involves the reaction between oxaloacetate
and acetyl CoA; Sufficient oxaloacetate must be present for the acetyl CoA
to react with.
Oxaloacetate concentration depends on pyruvate produced from glycolysis;
pyruvate can be converted to oxaloacetate by pyruvate carboxylase.
Certain body conditions upset the lipid-carbohydrate balance required for
the acetyl CoA generated by fatty acids to be processed by the TCA cycle:
(under these conditions, the problem of inadequate oxaloacetate arises)
Dietary intakes high in fat and low in carbohydrates
Diabetic conditions -- glucose not used properly
Prolonged fasting conditions
When oxaloacetate supplies are too low for all acetyl CoA to be processed
through the TCA cycle, ketogenesis takes place where excess acetyl CoA
is converted to ketone bodies

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Section 25.6

Ketone Bodies

Synthesis of ketone bodies from

acetyl CoA is primarily in liver
mitochondria
the three ketone bodies produced
are: acetoacetic acid, hydroxybutyric acid, and acetone;
they are carried by the blood to the
muscles and tissues where they are
converted back to acetoacetyl CoA
and then oxidized normally.
during diabetes, however, the
production of ketone bodies by the
liver exceeds the ability of the
muscles and tissues to oxidize them
so that they accumulate in the blood
ketosis is the overall accumulation
of ketone bodies in the blood
(ketonemia) and in the urine
(ketonuria)

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Section 25.6

Ketone Bodies

during ketosis acetone may be detected on the patients

breath because it is a volatile compound and is easily
excreted through the lungs

ketosis may occur with diabetes mellitus, in starvation, or

severe liver damage, or on a diet high in fats and low in
carbohydrates

during diabetes mellitus, the body is unable to oxidize

carbohydrates and instead oxidizes fats, leading to an
accumulation of ketone bodies in the blood and the urine;
the ketone bodies are acidic and tend to decrease the pH
of the blood leading to acidosis which may lead to a fatal
coma.

during acidosis, an increased amount of water intake is

needed to eliminate the products of metabolism. Unless
the water intake of a diabetic is increased, dehydration
will occur. Dehydration of diabetics may also be caused
by polyuria due to an increased amount of glucose in the
urine.

likewise, during prolonged starvation or on a high-fat, lowcarbohydrate diet, the body tends to burn fat instead of
carbohydrates, leading to ketosis and acidosis.

in severe liver damage, the liver cannot store glycogen in

the required amounts so that the carbohydrates are not
available for the normal oxidation of fats, leading to
ketosis
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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
called fatty acid synthase
catalyzes reactions

Enzymes are not complexed

and the steps are
independent

Intermediates bonded to
acyl carrier protein (ACP)

The carrier for fatty acid

spiral is CoA

Depends upon reducing

agent NADPH

Dependent upon oxidizing

agents FAD and NAD+

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Section 25.7

Biosynthesis of Fatty Acids: Lipogenesis

The CitrateMalate 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

Cytoplasmic acetyl CoA is

converted to malonyl CoA in
a carboxylation reaction that
involves CO2 and ATP.

The reaction occurs only

when cellular ATP levels are
high catalyzed by acetyl CoA
carboxylase complex, which
requires both Mn2+ and biotin
for its activity.
ACP (Acyl Carrier Protein)
Complex Formation:
All intermediates in fatty
acid synthesis are linked
to carrier proteins (ACPSH)
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 the steps 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

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Section 25.7

Biosynthesis of Fatty Acids: Lipogenesis

Chain Elongation
In the first turn of the fatty acid
biosynthetic pathway, acetyl ACP
is converted to butyryl ACP. In the
next cycle, the butyryl ACP reacts
with another malonyl ACP to
produce a 6-carbon acid.
Continued cycles produce acids
with 8, 10, 12, 14, and 16 carbon
atoms
elongation of the acyl group chain
through this procedure, which is
tied to the fatty acid synthase
complex, stops upon formation of
the C16 acyl group (palmitic
acid)
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Section 25.7

Biosynthesis of Fatty Acids: Lipogenesis

Unsaturated Fatty Acid Biosynthesis and
Essential FattyAcids

different enzyme systems and different cellular locations are

required for elongation of the chain beyond C16 and for introduction
of double bonds into the acyl group (unsaturated fatty acids)
production or unsaturated fatty acids (insertion of double bonds)
requires oxidation by molecular oxygen (O2), which combines with
the hydrogen that is removed to form water
in humans and animals, enzymes can introduce double bonds only
between C4 and C5 and between C9 and C10.
thus the important unsaturated fatty acids linoleic (C18 with C 9 and
C12 double bonds) and linolenic (C18 with C9, C12, and C15 double
bonds) cannot be biosynthesized.
They must be obtained from the diet. Plants have the necessary
enzymes to synthesize these acids.

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Section 25.9

Fate of Fatty-Acid Generated Acetyl CoA

Acetyl-CoA formed from fatty acids is further
channeled in various different routes:
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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Section 25.9

Fate of Fatty-Acid Generated Acetyl CoA

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, a C27 molecule, occur in liver and requires at least 15
acetyl CoAs and involves at least 27 separate enzymatic steps
once cholesterol has been formed, biosynthetic pathways are available to
convert it to each of the five major classes of steroid hormones: progestins,
androgens, estrogens, glucocorticoids, and mineralocorticoids, as well as bile
salts and vitamin D.

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Section 25.9

Fate of Fatty-Acid Generated Acetyl CoA

Overview of fat and sugar synthesis and

breakdown pathways

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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 of
oxidation of
glucose, glycerol
and fatty acids

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Section 25.11

B Vitamins and Carbohydrate Metabolism

Structurally modified B-vitamins

function as coenzymes in lipid
metabolism
6 B-Vitamins participate in
various pathways of lipid
metabolism:
Niacin NAD+ and NADH;
NADP + and NADPH
Riboflavin as FAD,
FADH2
Pantothenic acid - as CoA
Biotin
Without these B-vitamins body
would be unable to utilize lipids
as energy sources.

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