Lipid Metabolism pdf - Metabolism and Temperature Regulation

the juncture of the jugular and subclavian veins.

cholesterol, and 1 per cent apoprotein B. The chylomicrons are then transported

cipally of triglycerides, they also contain about 9 per cent phospholipids, 3 per cent

tract enter the chylomicrons. Thus, although the chylomicrons are composed prin-

to the lymphatic vessel walls.

to the outer surfaces of the chylomicrons. This leaves the remainder of the protein

ters are between 0.08 and 0.6 micron. A small amount of apoprotein B is adsorbed

chylomicrons,

enter the lymph as minute, dispersed droplets called

fatty acids. Then, while passing through the intestinal epithelial cells, the mono-

tinal lymph. During digestion, most triglycerides are split into monoglycerides and

tion of a few short-chain fatty acids, are absorbed from the intestines into the intes-

As explained in Chapter 65, almost all the fats in the diet, with the principal excep-

Gastrointestinal Tract by Lymph—The Chylomicrons

Transport of Triglycerides and Other Lipids from the

Transport of Lipids in the Body Fluids

an 18-carbon chain and is fully saturated with hydrogen atoms; (2)

(shown in the tristearin example above), which has

glycerol. The three fatty acids most commonly present in the triglycerides of the

Tristearin

with the utilization of triglycerides for energy, the following typical structure of the

Basic Chemical Structure of Triglycerides (Neutral Fat).

perform other cellular functions.

of triglycerides, are used to form the membranes of all cells of the body and to

However, some lipids, especially cholesterol, the phospholipids, and small amounts

metabolic processes, a function they share almost equally with the carbohydrates.

The triglycerides are used in the body mainly to provide energy for the different

many of the physical and chemical properties of other lipid substances.

sterol nucleus is synthesized from portions of fatty acid molecules, thus giving it

Although cholesterol does not contain fatty acid, its

acid, palmitic acid, is the following: CH

long-chain hydrocarbon organic acids. A typical fatty

fatty acids,

Chemically, the basic lipid moiety of the triglycerides

and (4) a few others of less importance.

cholesterol;

They include (1)

lipids.

840

Lipid Metabolism

Several chemical compounds in food and in the
body are classified as

neutral fat,

also known as triglycerides;

(2) phospholipids;

(3)

and the phospholipids is

which are simply

(CH

)

COOH.

Because most of this chapter deals

triglyceride molecule must be understood.

—(CH

)

—COO—CH

—(CH

)

—COO—CH

—(CH

)

—COO—CH

Note that three long-chain fatty acid molecules are bound with one molecule of

human body are (1) stearic acid

oleic acid, which

also has an 18-carbon chain but has one double bond in the middle of the chain;
and (3) palmitic acid, which has 16 carbon atoms and is fully saturated.

glycerides and fatty acids are resynthesized into new molecules of triglycerides that

whose diame-

molecules projecting into the surrounding water and thereby increases the suspen-
sion stability of the chylomicrons in the lymph fluid and prevents their adherence

Most of the cholesterol and phospholipids absorbed from the gastrointestinal

upward through the thoracic duct and emptied into the circulating venous blood at

and phospholipids.

high-density lipoproteins,

phospholipids; and (4)

erides, leaving an especially high concentration of

teins,

low-density lipopro-

phospholipids are increased; (3)

removed, so that the concentrations of cholesterol and

lipoproteins,

lesterol and phospholipids; (2)

lipoproteins,

very low density

as measured in the ultracentrifuge: (1)

major types of lipoproteins, classified by their densities

are themselves very large lipoproteins, there are four

Aside from the chylomicrons, which

Types of Lipoproteins.

Protein

200

Triglycerides

160

Phospholipids

160

Cholesterol

180

per 100 ml of plasma—that is, 700 mg/dl. This can be

The total concentration

phospholipids,

triglycerides, cholesterol,

smaller than chylomicrons, but qualitatively similar

These are small particles—much

form of

have been removed from the blood, more than 95

In the postabsorptive state, after all the chylomicrons

Cholesterol and Phospholipids

Function in Transporting

conditions.

transport is extreme. This shows how variable the rate

fatty acid combine with each molecule of albumin, but

Under normal conditions, only about 3 molecules of

energy from carbohydrates.

conditions, the person derives little or no metabolic

cases of starvation and in diabetes; in both these

eightfold. Such a large increase occurs especially in

fatty acid concentration in the blood; in fact, the

2. Conditions that increase the rate of utilization

energy.

by the oxidation of transported free fatty acids,

calculate that at this rate, almost all the normal

new fatty acid every 2 to 3 minutes.

half the plasma fatty acid is replaced by

the blood, its rate of “turnover” is extremely

1. Despite the minute amount of free fatty acid in

latory system. Strangely enough, even this small amount

under resting conditions is about 15 mg/dl, which is a

The concentration of free fatty acids in the plasma

substances.

of (1) esters of glycerol, (2) cholesterol, or (3) other

nonesterified fatty acids,

with albumin molecules of the plasma proteins. Fatty

plasma, and the ionic portion combines immediately

On leaving fat cells, fatty acids ionize strongly in the

This is discussed later in the chapter.

and this also promotes rapid hydrolysis of triglycerides.

vated by several hormones from the endocrine glands,

Second, a

of triglycerides, the result is hydrolysis of triglycerides.

also available in insufficient quantities. Because this

-glycerophosphate,

the glucose breakdown products,

of glucose available to the fat cell is inadequate, one of

in promoting this hydrolysis. First, when the amount

This is achieved by hydrolysis of the triglycerides

acids.

tissue. It is transported mainly in the form of

be used elsewhere in the body to provide energy, it must

When fat that has been stored in the adipose tissue is to

in the Blood in Combination

“Free Fatty Acids” Are Transported

in the cells in the same way.

phospholipids; this, too, releases fatty acids to be stored

later in the chapter. The lipase also causes hydrolysis of

metabolic processes of the storage cells, as discussed

triglycerides, with new glycerol being supplied by the

these cells, the fatty acids are again synthesized into

of the adipose tissue and into the liver cells. Once inside

branes of the cells, immediately diffuse into the fat cells

The fatty acids, being highly miscible with the mem-

come in contact with the endothelial wall, thus releas-

is especially active in the capillary endothelium, where

This enzyme

lipoprotein lipase.

liver. Both adipose tissue and the liver contain large

and Fat Is Stored in Adipose Tissue and Liver Cells.

Chylomicron Triglycerides Are Hydrolyzed by Lipoprotein Lipase,

chylomicrons is removed mainly in the following way.

becomes clear again within a few hours. The fat of the

crons have a half-life of less than 1 hour, so the plasma

turbid and sometimes yellow. However, the chylomi-

of the large size of the chylomicrons, the plasma appears

rise to 1 to 2 per cent of the total plasma, and because

of fat, the chylomicron concentration in the plasma may

Chapter 68

Lipid Metabolism

841

Removal of the Chylomicrons
from the Blood

About 1 hour after a meal that contains large quantities

Most of the

chylomicrons are removed from the circulating blood as
they pass through the capillaries of adipose tissue or the

quantities of the enzyme

it hydrolyzes the triglycerides of chylomicrons as they

ing fatty acids and glycerol.

with Albumin

first be transported from the adipose tissue to the other

free fatty

back into fatty acids and glycerol.

At least two classes of stimuli play important roles

substance is required to maintain the glycerol portion

hormone-sensitive cellular lipase can be acti-

acids bound in this manner are called free fatty acids
or

to distinguish them from

other fatty acids in the plasma that exist in the form

total of only 0.45 gram of fatty acids in the entire circu-

accounts for almost all the transport of fatty acids from
one part of the body to another for the following
reasons:

rapid:

One can

energy requirements of the body can be provided

without using any carbohydrates or proteins for

of fat for cellular energy also increase the free

concentration sometimes increases fivefold to

as many as 30 fatty acid molecules can combine with a
single albumin molecule when the need for fatty acid

of lipid transport can be under different physiologic

Lipoproteins—Their Special

per cent of all the lipids in the plasma are in the

lipoprotein.

in composition—containing

and protein.

of lipoproteins in the plasma averages about 700 mg

broken down into the following individual lipoprotein
constituents:

mg/dl of plasma

which contain high concentrations of

triglycerides and moderate concentrations of both cho-

intermediate-density

which are very low density lipoproteins

from which a share of the triglycerides has been

which are derived from intermediate-density

lipoproteins by the removal of almost all the triglyc-

cholesterol and a moderately high concentration of

which

contain a high concentration of protein (about 50 per
cent) but much smaller concentrations of cholesterol

The fatty acid molecule is degraded in the

stance. Once inside the mitochondria, fatty acids split

their transport into the mitochondria. This is a carrier-

Therefore, the first step for the use of fatty acids is

Entry of Fatty Acids into Mitochondria.

processed further in the following way.

the fatty acids can be used for energy, they must be

glucose breakdown and is thus used for energy. Before

phosphate,

Glycerol, on entering the active tissue, is immediately

cells—can use fatty acids for energy.

some exceptions, such as brain tissue and red blood

will be oxidized to give energy. Almost all cells—with

transported in the blood to the active tissues, where they

glycerol. Then, both the fatty acids and the glycerol are

The first stage in using triglyc-

Hydrolysis of Triglycerides.

fatty acids released from the triglycerides for energy.

triglycerides, then stored, and used later in the form of

of carbohydrates is. In addition, many of the carbohy-

calories derived from carbohydrates. Therefore, the use

diet are derived from fats, which is almost equal to the

About 40 per cent of the calories in a typical American

of Adenosine Triphosphate

for Energy: Formation

Use of Triglycerides

cells.

fats, and their principal source is the liver. This desatu-

tissues of the body, because many structural elements of

triglycerides of adipose tissue.This capability of the liver

tissues of desaturating fatty acids, so that liver triglyc-

Also, the liver cells are much more capable than other

terol, which are continually synthesized by the liver.

The liver cells, in addition to containing triglycerides,

lipids are being used for energy.

tions, the total amount of triglycerides in the liver is

dation begin. Thus, under normal physiologic condi-

in the liver, where the initial stages of much of fat degra-

fatty acids in the blood, and redeposited as triglycerides

mobilized from the adipose tissue, transported as free

these conditions, large quantities of triglycerides are

instead of carbohydrates is being used for energy. In

mellitus, and (3) in any other condition in which fat

(1) during the early stages of starvation, (2) in diabetes

fatty acids, especially cholesterol and phospholipids.

proteins as well; and (3) synthesize other lipids from

mainly from carbohydrates, but to a lesser extent from

can be used for energy; (2) synthesize triglycerides,

The principal functions of the liver in lipid metabolism

Liver Lipids

not the same fat that was stored last month, thus empha-

fat cells are renewed about once every 2 to 3 weeks,

of the rapid exchange of fatty acids, the triglycerides in

erides of the fat cells to release free fatty acids. Because

activated by hormones, cause splitting of the triglyc-

from the chylomicrons and lipoproteins. Others, when

lipases are present in adipose tissue. Some of these

As discussed earlier, large quantities of

Tissue Lipases.

Exchange of Fat Between the Adipose Tissue and the Blood—

later in the chapter.

supplements the synthesis of fat in the liver, as discussed

acids and triglycerides from carbohydrates; this function

Fat cells can synthesize very small amounts of fatty

the cells.

in a liquid state. This is particularly important, because

melting point, thereby always allowing the fat to remain

the cell triglycerides, over a period of weeks, become

are exposed to prolonged cold, the fatty acid chains of

fat cells are generally in a liquid form. When the tissues

cent of the entire cell volume. Triglycerides inside the

The fat cells (adipocytes) of

provide heat insulation for the body, as discussed in

elsewhere in the body. A subsidiary function is to

The major function of adipose tissue is storage of

fat deposits,

The adipose

liver.

of the body, the

Adipose Tissue

the insides of arterial walls.

atherosclerosis,

periphery back to the liver. Later in the chapter, we

in the liver mainly to the adipose tissue, whereas the

port their lipid components in the blood. The very low

The primary function of the lipoproteins is to trans-

acids from the intestines.

triglycerides are synthesized. In addition, small quanti-

most of the plasma cholesterol, phospholipids, and

lipoproteins are formed in the liver, which is also where

Metabolism and Temperature Regulation

842

Unit XIII

Formation and Function of Lipoproteins.

Almost all the

ties of high-density lipoproteins are synthesized in the
intestinal epithelium during the absorption of fatty

density lipoproteins transport triglycerides synthesized

other lipoproteins are especially important in the dif-
ferent stages of phospholipid and cholesterol transport
from the liver to the peripheral tissues or from the

discuss in more detail special problems of cholesterol
transport in relation to the disease

which

is associated with the development of fatty lesions on

Fat Deposits

Large quantities of fat are stored in two major tissues

adipose tissue and the

tissue is usually called

or simply tissue fat.

triglycerides until they are needed to provide energy

Chapter 73.

Fat Cells (Adipocytes).

adipose tissue are modified fibroblasts that store almost
pure triglycerides in quantities as great as 80 to 95 per

either shorter or more unsaturated to decrease their

only liquid fat can be hydrolyzed and transported from

enzymes catalyze the deposition of cell triglycerides

which means that the fat stored in the tissues today is

sizing the dynamic state of storage fat.

are to (1) degrade fatty acids into small compounds that

Large quantities of triglycerides appear in the liver

determined to a great extent by the overall rate at which

contain large quantities of phospholipids and choles-

erides normally are much more unsaturated than the

to desaturate fatty acids is functionally important to all

all cells contain reasonable quantities of unsaturated

ration is accomplished by a dehydrogenase in the liver

of fats by the body for energy is as important as the use

drates ingested with each meal are converted into

erides for energy is their hydrolysis into fatty acids and

changed by intracellular enzymes into glycerol-3-

which enters the glycolytic pathway for

Degradation and oxi-

dation of fatty acids occur only in the mitochondria.

mediated process that uses carnitine as the carrier sub-

away from carnitine and are degraded and oxidized.

Degradation of Fatty Acids to Acetyl Coenzyme A by Beta-
Oxidation.

Chapter 67. The net reaction in the citric acid cycle for

of the mitochondria,

chemiosmotic oxidative system

dioxide and hydrogen atoms. The hydrogen is subse-

form citric acid, which then is degraded into carbon

Chapter 67), combining first with oxaloacetic acid to

The acetyl-CoA molecules

ecule at the same time, entirely separate from the

addition to the released acetyl-CoA molecules, four

original fatty acid molecule by another two carbons. In

still another acetyl-CoA molecule, thus shortening the

2 and progresses through equations 3, 4, and 5 to release

Next, this shorter fatty acyl-CoA enters into equation

molecule; this time, however, the molecule is two carbon

fatty acid molecule, and this forms a new fatty acyl-CoA

into the cell fluid. At the same time, another CoA mol-

Then, in equation 5, the right-hand two-carbon

is, the beta carbon becomes oxidized.

the fatty acyl-CoA binds with an oxygen molecule—that

4, the

A (CoA) to form fatty acyl-CoA. In equations 2, 3, and

oxidation process, note that in equation 1 the first step

To understand the essential steps in the beta-

process for degradation of fatty acids.

beta-oxidation

This process, which is shown in Figure 68–1, is called the

acetyl coenzyme A

Chapter 68

Lipid Metabolism

843

mitochondria by progressive release of two-carbon seg-
ments in the form of

(acetyl-CoA).

is combination of the fatty acid molecule with coenzyme

beta carbon (the second carbon from the right) of

portion of the molecule is split off to release acetyl-CoA

ecule binds at the end of the remaining portion of the

atoms shorter because of the loss of the first acetyl-CoA
from its terminal end.

atoms of hydrogen are released from the fatty acid mol-

acetyl-CoA.

Oxidation of Acetyl-CoA.

formed by beta-oxidation of fatty acids in the mito-
chondria enter immediately into the citric acid cycle (see

quently oxidized by the

which was also explained in

each molecule of acetyl-CoA is the following:

Citric acid cycle

H + HCo-A + ATP + Oxaloacetic acid

CH COCo-A + Oxaloacetic acid

H O + ADP

ææææææ

ATP.

acid molecule, making a

stearic acid. However, two high-energy bonds are con-

metabolized. Thus, a total of 148 molecules of ATP are

gen), one for each of the 9 acetyl-CoA molecules

rate from the ATP released by the oxidation of hydro-

of ATP are formed in the citric acid cycle itself (sepa-

from each molecule of stearic acid. Another 9 molecules

of ATP formed by the oxidation of hydrogen derived

gens. This makes 34 plus 105, or a total of 139 molecules

synthesized for each of the 70 NADH and H

avoprotein hydrogens, and 1.5 molecules of ATP are

1 molecule of ATP is synthesized for each of the 34

enter the oxidative system at different points, so that

the mitochondria, as discussed in Chapter 67, but they

These two groups of hydrogen atoms are oxidized in

as NADH and H

removed by nicotinamide adenine dinucleotide (NAD

avoproteins, and 70 are

acid molecule. Of this group, 34 are removed from

hydrogens. This makes a total of 104 hydrogen atoms

more hydrogen atoms are removed, making another 72

are subsequently degraded by the citric acid cycle, 8

addition, for each of the 9 molecules of acetyl-CoA that

molecules, 32 extra hydrogen atoms are removed. In

. Therefore, for every stearic

, NADH, and H

FADH

1, note that the 4 separate hydrogen

In Figure 68

Tremendous Amounts of ATP Are Formed by Oxidation of Fatty

triphosphate (ATP).

oxidation, liberating large amounts of adenosine

system of the mitochondria

chemiosmotic oxidative

metabolism of glucose. And the extra hydrogen atoms

CoA, their

Thus, after initial degradation of fatty acids to acetyl-

final breakdown is precisely the same as that

of the acetyl-CoA formed from pyruvic acid during the

are also oxidized by the same

that is used in carbohydrate

Acids.

–

atoms released each time a molecule of acetyl-CoA is
split from the fatty acid chain are released in the forms

fatty acid molecule that is split to form 9 acetyl-CoA

eventually released by the degradation of each stearic

the degrading fatty acids by fl

)

hydro-

formed during the complete oxidation of 1 molecule of

sumed in the initial combination of CoA with the stearic

net gain of 146 molecules of

CH=CHCOCoA + H

(Fatty acyl-CoA) (Acetyl-CoA)

AMP

COCoA

CH=CHCOCoA + FADH

COCoA + CH

COCoA + CoA

COCoA + NADH + H

COCoA + NAD

COCoA + FAD

COOH + CoA + ATP

(1) RCH

(Fatty acid)

Thiokinase

Acyl dehydrogenase

Enoyl hydrase

dehydrogenase

Thiolase

-Hydroxyacyl

(2) RCH

(4) RCH

CHOHCH

RCH

COCH

(5) RCH

COCH

RCH

COCoA

RCH

CHOHCH

COCoA

RCH

Pyrophosphate

(Fatty acyl-CoA)

(3) RCH

Figure 68–1

Beta-oxidation of fatty acids to yield acetyl coenzyme A.

almost entirely of fat. In all these states, essentially no

occurs especially in starvation, in diabetes mellitus, and

Ketosis

ketone bodies.

The three compounds are called

ketosis,

uids; this condition

The con-

Ketosis in Starvation, Diabetes, and Other Diseases.

fusion into the cells.

the target cells, which allows almost instantaneous dif-

transport. The rapid transport of both these substances

actually transported, as is also true for free fatty acid

in the blood, large

plasma seldom rises above 3 mg/dl. Yet despite this

Normally, the acetoacetic acid and

oxidized for energy, as already explained.

formed. These in turn enter the citric acid cycle and are

tissues. Here they again diffuse into the cells, where

-hydroxybutyric acid, and

The acetoacetic acid,

-hydroxybutyric acid,

for energy. The chemical processes are the following:

to the other cells throughout the body, where it is used

acetoacetic acid, which is then transported in the blood

acid chains have been split into acetyl-CoA, two mole-

intrinsic metabolic processes. Instead, when the fatty

of lipids are being used for energy. However, the liver

occurs in the liver, especially when excessive amounts

in the Liver and Its Transport

Formation of Acetoacetic Acid

Metabolism and Temperature Regulation

844

Unit XIII

in the Blood

A large share of the initial degradation of fatty acids

uses only a small proportion of the fatty acids for its own

cules of acetyl-CoA condense to form one molecule of

Part of the acetoacetic acid is also converted into

and minute quantities are

converted into acetone in accord with the following
reactions:

acetone diffuse freely through the liver cell membranes
and are transported by the blood to the peripheral

reverse reactions occur and acetyl-CoA molecules are

b-hydroxybutyric

acid that enter the blood are transported so rapidly to
the tissues that their combined concentration in the

small concentration

quantities are

results from their high solubility in the membranes of

centrations of acetoacetic acid,

b-hydroxybutyric acid,

and acetone occasionally rise to levels many times
normal in the blood and interstitial fl
is called

because acetoacetic acid is a keto acid.

sometimes even when a person’s diet is composed

Acetoacetic acid

Acetone

+ 2H

-CO

b-Hydroxybutyric acid

Acetoacetic acid

Acetyl CoA

CH COCH COOH

HCo-A

CH COCo-A + H O

liver cells

other cells

ææææ

The

teins to the adipose tissue, where they are stored.

the adipose tissue itself. The triglycerides formed in the

the liver, but minute quantities are also synthesized in

In human beings, most triglyceride synthesis occurs in

form in the adipose tissue.

can be stored in the form of glycogen, the excess is

Whenever a greater quantity of carbohydrates enters

from Carbohydrates

Synthesis of Triglycerides

fats.

glucose, can derive 50 to 75 per cent of their energy from

by the cells. After a few weeks, even the brain cells,

clear, enhance the rate of acetoacetic acid metabolism

ketosis. Undoubtedly, several factors, none of which is

times live almost entirely on a fat diet, do not develop

not occur. For instance, the Inuit (Eskimos), who some-

than usual, and in this instance, ketosis normally does

a carbohydrate diet to an almost completely fat diet, a

When changing slowly from

criterion of ketosis.

ties in the expired air of the lungs. This gives the breath

substance, some of which is blown off in small quanti-

The acetone that is formed during ketosis is a volatile

20 times normal, thus leading to extreme acidosis, as

liver, the blood concentrations of acetoacetic acid and

entry of acetyl-CoA into the citric acid cycle, and when

ciency

processed in the citric acid cycle. Therefore, de

oxaloacetate

most important reason is the following: One of the prod-

the amount of ketone bodies that can be oxidized; the

to the cells. For several reasons, the cells are limited in

The ketone bodies pour out of the liver to be carried

acids is converted to ketone bodies.

energy and (2) to the liver cells, where much of the fatty

result, tremendous quantities of fatty acids become

the removal of fatty acids from the fat tissues. As a

secretion of glucagon by the pancreas, and decreased

tion of glucocorticoids by the adrenal cortex, increased

tion, several hormonal factors

of removal of fatty acids from adipose tissues; in addi-

of fats. We shall see later in the chapter that the unavail-

When carbohydrates are not used for energy, almost

glucose transport into the cells.

a high-fat diet because carbohydrates are not available,

carbohydrates are metabolized—in starvation and with

and in diabetes because insulin is not available to cause

all the energy of the body must come from metabolism

ability of carbohydrates automatically increases the rate

—such as increased secre-

secretion of insulin by the pancreas—further enhance

available (1) to the peripheral tissue cells to be used for

ucts of carbohydrate metabolism is the

that

is required to bind with acetyl-CoA before it can be

of oxaloacetate derived from carbohydrates limits the

there is a simultaneous outpouring of large quantities
of acetoacetic acid and other ketone bodies from the

b-hydroxybutyric acid sometimes rise to as high as

explained in Chapter 30.

an acetone smell that is frequently used as a diagnostic

Adaptation to a High-Fat Diet.

person’s body adapts to use far more acetoacetic acid

which normally derive almost all their energy from

the body than can be used immediately for energy or

rapidly converted into triglycerides and stored in this

liver are transported mainly in very low density lipopro-

Conversion of Acetyl-CoA into Fatty Acids.

first step

in the synthesis of triglycerides is conversion of

use as proteins, a large share of the excess is stored as

synthesized into triglycerides. Therefore, when people

discussed in Chapter 69. The acetyl-CoA can then be

Many amino acids can be converted into acetyl-CoA, as

from Proteins

Synthesis of Triglycerides

cult for the tissues to form triglycerides.

-glycerophosphate, which also

Second, lack of glucose in the fat cells greatly reduces

needed for fat synthesis can be derived from glucose.

factorily, so that little of the acetyl-CoA and NADPH

able, glucose does not enter the fat and liver cells satis-

for the following reasons: First, when insulin is not avail-

diabetes mellitus, fats are poorly synthesized, if at all,

When no insulin is available, as occurs in serious

an animal must be highly motile to survive.

carbohydrate, which is exceedingly important when

gain, a person can store several times as much

gram of glycogen. Therefore, for a given weight

2. Each gram of fat contains almost two and a half

as stored in the form of carbohydrate.

later use. Indeed, the average person has almost

can be stored. Therefore, fat synthesis provides a

put together. In contrast, many kilograms of fat

skeletal muscles, and all other tissues of the body

grams of glycogen can be stored in the liver, the

generally slight; a maximum of only a few hundred

1. The ability of the different cells of the body to

Fat synthesis from

triglycerides.

energy in the glucose is lost in the form of heat; the

eride synthesis, only about 15 per cent of the original

of glucose degradation. This mechanism is discussed in

-glycerophosphate, which

3, the glycerol portion of

As shown in Figure 68

in the body.

chain lengths of 14 carbon atoms or greater, a factor that

glycerol to form triglycerides. The enzymes that cause

grown to contain 14 to 18 carbon atoms, they bind with

Triglycerides.

-Glycerophosphate to Form

polymerization process.

and NADPH as the principal intermediates in the

2, using

two-step process shown in Figure 68

degradation described earlier. Instead, this occurs by the

acids. However, the synthesis of fatty acids from acetyl-

are actually large polymers of acetic acid, it is easy to

of glucose by the glycolytic system. Because fatty acids

Chapter 67, this occurs during the normal degradation

carbohydrates into acetyl-CoA. As explained in

Chapter 68

Lipid Metabolism

845

understand how acetyl-CoA can be converted into fatty

CoA is not achieved by simply reversing the oxidative

–

malonyl-

CoA

Combination of Fatty Acids with a

Once the synthesized fatty acid chains have

this conversion are highly specific for fatty acids with

controls the physical quality of the triglycerides stored

–

triglycerides is furnished by

is another product derived from the glycolytic scheme

Chapter 67.

Efficiency of Carbohydrate Conversion into Fat.

During triglyc-

remaining 85 per cent is transferred to the stored

Importance of Fat Synthesis and Storage.

carbohydrates is especially important for two reasons:

store carbohydrates in the form of glycogen is

means by which the energy of excess ingested
carbohydrates (and proteins) can be stored for

150 times as much energy stored in the form of fat

times the calories of energy contained by each

energy in the form of fat as in the form of

Failure to Synthesize Fats from Carbohydrates in the Absence of
Insulin.

the availability of

makes it diffi

have more proteins in their diets than their tissues can

fat.

9CoA

Malonyl-CoA

1 Acetyl-CoA

CoA

ADP

ATP

COCoA

(Acetyl-CoA carboxylase)

COOH

–3

16NADPH

16H

1 Steric acid

8CO

16NADP

Step 1:

Step 2:

Malonyl-CoA

Figure 68–2

Synthesis of fatty acids.

Acetyl-CoA

Triglycerides

Glucose

Fatty acids

-Glycerophosphate

NADH

NADPH

Glycolytic

pathway

Pentose

phosphate

pathway

triglycerides from glucose.

Figure 68–3

Overall schema for synthesis of

cephalins,

lecithins,

The major types of body phospholipids are

Cholesterol

stores, resulting in severe obesity.

storage of fat continue normally. Such a one-way

adipose tissue by tissue lipase, while synthesis and

occurs. In at least one of these, the obesity is

adipose tissue, to be used later for energy.

or proteins, is then stored almost entirely as fat in the

for energy. The excess food, whether fats, carbohydrates,

y, it is caused by the ingestion of

balances, but brie

Obesity means deposition of excess fat in the body. This

hormone.

The effects of the different hormones on metabolism

uence of this hormone. The

of fat, which is believed to result indirectly from an

Finally,

activating hormone-sensitive lipase. Therefore, growth

Growth hormone

a great extent that ketosis results. Corticotropin and

s disease, fats are frequently mobilized to such

long periods, as occurs in the endocrine condition called

nephrine or a similar lipase. When corticotropin and

glucocorticoids.

be released by the anterior pituitary gland, and this

mobilization and utilization in a similar manner.

increased. Other types of stress that activate the sym-

rises as much as eightfold, and the use of these fatty

and mobilization of fatty acids. Sometimes the free fatty

cells, and this causes rapid breakdown of triglycerides

eride lipase,

cise, as a result of sympathetic stimulation. These two

utilization is that observed during heavy exercise. This

noted here.

insulin lack,

cant effects on fat utilization. Some important

carbohydrates.

but also decreases fat storage, which further shifts the

caused by the absence of carbohydrates. This not only

adipose tissue. Among the most important of these is

used for energy in place of carbohydrates.

direction, and fat is mobilized from the adipose cells and

not available. The equilibrium shifts in the opposite

converted to fat for storage.

acts as a fat-sparer but also increases fat stores. In fact,

Thus, an excess of carbohydrates in the diet not only

automatically causing increased synthesis of fatty acids.

drates are being used, these intermediates increase,

mediates of the citric acid cycle. When excess carbohy-

acetyl-CoA carboxylase,

malonyl-CoA. The rate of this reaction is controlled

rst step, which is the rate-limiting step, in the synthesis

conversion of carbohydrates to fats is the following: The

ate for the conversion of acetyl-CoA into fatty acids.

in the adipose tissue, thus creating conditions appropri-

degraded. This effect is caused partially by the large

Second, when carbohydrates are available in excess,

automatically inhibits the use of fatty acids for energy.

metabolism, the availability of large amounts of glucose

are available to be used for energy. Because

consequently, only minute quantities of fatty acids

result, the equilibrium between free fatty acids and

free fatty acids in the form of stored triglycerides. As a

available), the excess

other.When excess quantities of

fatty acids. They are in constant equilibrium with each

forms: stored triglycerides and small quantities of free

lowing: The fats in adipose tissue cells are present in two

carbohydrates. One of the most important is the fol-

There are several reasons for this

are used preferentially over triglycerides for energy.

carbohydrates are available in the body, carbohydrates

When excess quantities of

Carbohydrates Are Available.

Release from Triglycerides

Regulation of Energy

Metabolism and Temperature Regulation

846

Unit XIII

Carbohydrates Are Preferred over Fats for Energy When Excess

“fat-sparing” effect of

a-glycerophosphate are

present (which occurs when excess carbohydrates are

a-glycerophosphate binds the

triglycerides shifts toward the stored triglycerides;

glycerophosphate is an important product of glucose

fatty acids are synthesized more rapidly than they are

quantities of acetyl-CoA formed from the carbohy-
drates and by the low concentration of free fatty acids

An even more important effect that promotes the

fi
of fatty acids is carboxylation of acetyl-CoA to form

primarily by the enzyme

the

activity of which is accelerated in the presence of inter-

all the excess carbohydrates not used for energy or
stored in the small glycogen deposits of the body are

Acceleration of Fat Utilization for Energy in the Absence of Car-
bohydrates.

All the fat-sparing effects of carbohydrates

are lost and actually reversed when carbohydrates are

Also important are several hormonal changes that

take place to promote rapid fatty acid mobilization from

a marked decrease in pancreatic secretion of insulin

reduces the rate of glucose utilization by the tissues

equilibrium in favor of fat metabolism in place of

Hormonal Regulation of Fat Utilization.

At least seven of

the hormones secreted by the endocrine glands have
signifi
hormonal effects on fat metabolism—in addition to

discussed in the previous paragraph—are

Probably the most dramatic increase that occurs in fat

results almost entirely from release of epinephrine and
norepinephrine by the adrenal medullae during exer-

hormones directly activate hormone-sensitive triglyc-

which is present in abundance in the fat

acid concentration in the blood of an exercising person

acids by the muscles for energy is correspondingly

pathetic nervous system can also increase fatty acid

Stress also causes large quantities of corticotropin to

causes the adrenal cortex to secrete extra quantities of

Both corticotropin and glucocorticoids

activate either the same hormone-sensitive triglyceride
lipase as that activated by epinephrine and norepi-

glucocorticoids are secreted in excessive amounts for

Cushing’

glucocorticoids are then said to have a ketogenic effect.

has an effect similar to but weaker

than that of corticotropin and glucocorticoids in

hormone can also have a mild ketogenic effect.

thyroid hormone causes rapid mobilization

increased overall rate of energy metabolism in all cells
of the body under the infl
resulting reduction in acetyl-CoA and other intermedi-
ates of both fat and carbohydrate metabolism in the
cells is a stimulus to fat mobilization.

are discussed further in the chapters dealing with each

Obesity

subject is discussed in Chapter 71 in relation to dietary

greater amounts of food than can be used by the body

Strains of rats have been found in which hereditary

obesity
caused by ineffective mobilization of fat from the

process causes progressive enhancement of the fat

Phospholipids and

Phospholipids

and sphingomyelin; their typical chemical

the liver, but all other cells of the body form at least

endogenous cho-

formed in the cells of the body, called

exogenous cholesterol,

each day from the gastrointestinal tract, which is called

form of cholesterol esters.

esters with fatty acids. Indeed, about 70 per cent of the

soluble in water. It is speci

intestinal lymph. It is highly fat soluble but only slightly

5, is present in the diets of all people, and it can be

Cholesterol, the formula of which is shown in Figure

cells throughout the body, as discussed in the next

the tissues. (5) Perhaps the most important of all the

bers. (4) Phos-

nervous system; this substance acts as an electrical insu-

ting process, is composed mainly of one of the cephalins.

(2) Thromboplastin, which is needed to initiate the clot-

of transport of cholesterol and other lipids can occur.

of most of these; in their absence, serious abnormalities

phospholipids are the following: (1) Phospholipids

Specific Uses of Phospholipids.

mation of some cephalins.

lecithin molecule. Also,

lecithin, because choline is the nitrogenous base of the

thesized in the body, is needed for the formation of

choline,

For instance,

are needed for the formation of some phospholipids.

tion increases. Also, certain speci

deposited in the liver, the rate of phospholipid forma-

rate of fat metabolism because, when triglycerides are

The rate of phospholipid formation is governed to

Probably 90 per cent are formed in the liver cells; sub-

in essentially all cells of the body, although certain cells

membranes and intracellular membranes.

body for various structural purposes, such as in cell

transported in lipoproteins, and used throughout the

properties are similar because they are all lipid soluble,

phospholipids are somewhat variant, their physical

nitrogenous base. Although the chemical structures of

one phosphoric acid radical, and they usually contain a

4. Phospholipids

formulas are shown in Figure 68

Chapter 68

Lipid Metabolism

847

–

always contain one or more fatty acid molecules and

Formation of Phospholipids.

Phospholipids are synthesized

have a special ability to form great quantities of them.

stantial quantities are also formed by the intestinal
epithelial cells during lipid absorption from the gut.

some extent by the usual factors that control the overall

fic chemical substances

either obtained in the diet or syn-

inositol is needed for the for-

Several functions of the

are an important constituent of lipoproteins in the
blood and are essential for the formation and function

(3) Large quantities of sphingomyelin are present in the

lator in the myelin sheath around nerve fi
pholipids are donors of phosphate radicals when these
radicals are needed for different chemical reactions in

functions of phospholipids is participation in the for-
mation of structural elements—mainly membranes—in

section of this chapter in connection with a similar func-
tion for cholesterol.

Cholesterol

68–
absorbed slowly from the gastrointestinal tract into the

fically capable of forming

cholesterol in the lipoproteins of the plasma is in the

Formation of Cholesterol.

Besides the cholesterol absorbed

an even greater quantity is

lesterol. Essentially all the endogenous cholesterol that
circulates in the lipoproteins of the plasma is formed by

(CH

)

(CH

)

(CH

)

(CH

)

(CH

)

(CH

)

(CH

)

(CH

)

A lecithin

A cephalin

Sphingomyelin

Typical phospholipids.

Figure 68–4

(CH

)

Cholesterol.

Figure 68–5

of the vessel wall, and

the endothelium, enter the

). The monocytes cross

at the site of injury (Figure 68

endothelium occurs, circulating monocytes and lipids

to the endothelium. After damage to the vascular

adhesion of macromolecules, platelets, and monocytes

. This, in turn,

of all sizes.

, in contrast, is a general

arterial walls.

Atherosclerosis

properties.

rates measured in months or years. For instance, their

uids.

lipids, cholesterol, and certain insoluble proteins. The

and some proteins. Thus, the physical integrity of cells

soluble in water must be available. In general, the only

For membranes to be formed, substances that are not

membranes.

organelles of all cells. It is also known that the

Chapter 2, it was pointed out that large quantities of

mainly membranes, in all cells of the body. In

with their function of forming specialized structures,

The previously mentioned uses of phospholipids and

Cellular Structural Functions of

400 milliliters.

skin; without this protection, the amount of evaporation

otherwise easily penetrate the body. Also, these lipid

agents, because cholesterol and the other skin lipids are

the skin highly resistant to the absorption of water-

corneum of the skin. This, along with other lipids, makes

endocrinology.

mones from them, as discussed in the chapters on

These glands can

testosterone.

adrenocortical hormones,

and absorption of fats.

substances to form bile salts, which promote digestion

explained in Chapter 70, this is conjugated with other

per cent of cholesterol is converted into cholic acid. As

body is to form cholic acid in the liver. As much as 80

Specific Uses of Cholesterol in the Body.

substances.

These effects are probably caused mainly by

blood cholesterol concentration, whereas excess

Lack of insulin

present-day dietary strategy.

mechanism of this effect is unknown, despite the

concentration a slight to moderate amount. The

3. Ingestion of fat containing highly

important, if not more important, to maintain a diet

cholesterol concentration, it is usually just as

of cholesterol. Therefore, to decrease the blood

results from increased fat deposition in the liver,

cholesterol concentration 15 to 25 per cent. This

2. A

markedly.

diet, although the response of individuals differs

in plasma cholesterol concentration. As a result,

reductase, thus providing an intrinsic feedback

of cholesterol, 3-hydroxy-3-methylglutaryl CoA

slightly. However, when cholesterol is ingested,

each day

amount of cholesterol ingested

1. An increase in the

secreted by the adrenal cortex, the ovaries, and the

in the liver; and (3) many important steroid hormones

(2) cholic acid, which is the basis of the bile acids formed

acetyl-CoA. In turn, the sterol nucleus can be modi

This is synthesized entirely from multiple molecules of

The basic structure of cholesterol is a sterol nucleus.

tially composed of this substance.

some cholesterol, which is consistent with the fact that

Metabolism and Temperature Regulation

848

Unit XIII

many of the membranous structures of all cells are par-

fied

by means of various side chains to form (1) cholesterol;

testes (these hormones are discussed in later chapters).

Factors That Affect Plasma Cholesterol Concentration—Feed-
back Control of Body Cholesterol.

Among the important

factors that affect plasma cholesterol concentration are
the following:

increases the plasma concentration

the rising concentration of cholesterol inhibits the
most essential enzyme for endogenous synthesis

control system to prevent an excessive increase

plasma cholesterol concentration usually is not
changed upward or downward more than

±15 per

cent by altering the amount of cholesterol in the

highly saturated fat diet increases blood

which then provides increased quantities of
acetyl-CoA in the liver cells for the production

low in saturated fat as to maintain a diet low in
cholesterol.

unsaturated fatty

acids usually depresses the blood cholesterol

fact that this observation is the basis of much

or thyroid hormone increases the

thyroid hormone decreases the concentration.

changes in the degree of activation of specific
enzymes responsible for the metabolism of lipid

By far the most

abundant nonmembranous use of cholesterol in the

A small quantity of cholesterol is used by (1) the

adrenal glands to form

(2)

the ovaries to form progesterone and estrogen, and (3)
the testes to form
also synthesize their own sterols and then form hor-

A large amount of cholesterol is precipitated in the

soluble substances and to the action of many chemical

highly inert to acids and to many solvents that might

substances help prevent water evaporation from the

can be 5 to 10 liters per day (as occurs in burn patients
who have lost their skin) instead of the usual 300 to

Phospholipids and Cholesterol—
Especially for Membranes

cholesterol are of only minor importance in comparison

phospholipids and cholesterol are present in both the
cell membrane and the membranes of the internal

ratio

of membrane cholesterol to phospholipids is especially
important in determining the fluidity of the cell

substances in the body that are not soluble in water
(besides the inorganic substances of bone) are the lipids

everywhere in the body is based mainly on phospho-

polar charges on the phospholipids also reduce the
interfacial tension between the cell membranes and
the surrounding fl

Another fact that indicates the importance of phos-

pholipids and cholesterol for the formation of structural
elements of the cells is the slow turnover rates of
these substances in most nonhepatic tissues—turnover

function in brain cells to provide memory processes
is related mainly to their indestructible physical

Atherosclerosis is a disease of the large and intermedi-
ate-sized arteries in which fatty lesions called athero-
matous plaques develop on the inside surfaces of the

Arteriosclerosis

term that refers to thickened and stiffened blood vessels

One abnormality that can be measured very early

in blood vessels that later become atherosclerotic is
damage to the vascular endothelium
increases the expression of adhesion molecules on
endothelial cells and decreases their ability to release
nitric oxide and other substances that help prevent

(mostly low-density lipoproteins) begin to accumulate

–6A

intima

Chapter 68

Lipid Metabolism

849

Adhesion

molecule

Damaged

endothelium

Lipoprotein

particle

Normal

artery

Lipid

droplets

Macrophage

foam cell

Growth/
inflammatory
factors

Receptor

Arterial

intima

Arterial

lumen

Blood monocyte

Monocyte

adhered to

epithelium

Monocyte

migrating

into intima

Intima

Endothelium

Media

Smooth
muscle
cells

Adventitia

Thrombosis

of a ruptured

plaque

Large

plaque

Small

plaque

that can make the arteries rigid tubes. Both of these

lipids of the plaques, leading to bony-hard calci

arteries become stiff and unyielding. Still later, calcium

without occlusion, the

ow, sometimes completely occluding the vessel. Even

arterial wall. The lipid deposits plus the cellular prolif-

). Also, the macrophages release substances that

proliferate to form larger and larger plaques (see Figure

With time, the fatty streaks grow larger and coalesce,

giving the macrophages a foamlike appearance. These

ingest and oxidize the accumulated lipoproteins,

macrophages,

ulate and form a thrombus. (Modified from Libby P: Inflammation in atherosclerosis. Nature 420:868, 2002.)

ry to coag-

to grow larger and accumulate lipids. Eventually, the plaque could occlude the vessel or rupture, causing the blood in the arte

Additional accumulation of macrophages and growth of the intima cause the plaque

cause inflammation and growth of the intimal layer.

macrophage then ingests and oxidizes lipoprotein molecules, becoming a macrophage foam cell. The foam cells release substances

The monocyte then migrates through the endothelium into the intimal layer of the arterial wall and is transformed into a macrop

Attachment of a monocyte to an adhesion molecule on a damaged endothelial cell of an artery.

Development of atherosclerotic plaque.

Figure 68–6

hage. The

that

differentiate to become

which then

macrophage foam cells then aggregate on the blood
vessel and form a visible fatty streak.

and the surrounding fibrous and smooth muscle tissues

68–6B
cause inflammation and further proliferation of smooth
muscle and fibrous tissue on the inside surfaces of the

eration can become so large that the plaque bulges into
the lumen of the artery and greatly reduces blood
fl

fibroblasts of the plaque eventu-

ally deposit extensive amounts of dense connective
tissue; sclerosis (fibrosis) becomes so great that the

salts often precipitate with the cholesterol and other

fications

atherosclerosis. Most of the cholesterol formed in the

diabetes develops; and (4) avoiding cigarette smoking.

if hypertension does develop; (3) effectively controlling

healthy diet and being physically active, or effectively

content; (2) preventing hypertension by maintaining a

weight, being physically active, and eating a diet that

The most important measures to protect against the

Prevention of Atherosclerosis

the incidence of atherosclerosis. The precise mecha-

density lipoprotein called lipoprotein(a), containing an

icals in the blood that damage the vessel walls. About

can lead to atherosclerosis, perhaps by forming free rad-

To add to the complexity of atherosclerosis, experi-

in the plasma. Others, such as hypertension, lead to

might be protective.

atherogenic or, conversely, that female sex hormones

rable age, suggesting that male sex hormones might be

In early and middle adulthood, men are more likely

stroke, and kidney disease.

atherosclerosis, which in turn may lead to heart attack,

do occur together, greatly increasing their risk for

overweight and obese patients, these three risk factors

increase the risk of developing atherosclerosis. In many

artery disease is increased almost 20-fold, suggesting

are all present, the risk for atherosclerotic coronary

when hypertension, diabetes mellitus, and hyperlipemia

artery disease is increased by more than eightfold. And

diabetes mellitus occur together, the risk for coronary

oping coronary artery disease. When hypertension and

on average, more than a twofold increased risk of devel-

twofold. Likewise, a person with diabetes mellitus has,

Hypertension, for example, increases the risk for

cigarette smoking.

and (5)

diabetes mellitus,

obesity,

terol and lipoproteins, atherosclerosis still develops.

high-density to low-density lipoproteins, the likelihood

Consequently, when a person has a high

protect against the development of atherosclerosis.

nism is true or not, high-density lipoproteins do help

to be deposited in arterial walls. Whether this mecha-

teins. It is believed that high-density lipoproteins can

rotic blockage of blood vessels throughout the body.

to 1000 mg/dl, levels that are four to six times normal.

plasma increases immensely.

plasma cholesterol. As a result, the number of very low

rampage, producing new cholesterol; it is no longer

or low-density lipoproteins. Without this absorption, the

tors, the liver cannot absorb either intermediate-density

s cells. In the absence of these recep-

This is a disease in which

throughout their arterial systems.

because of their vegetarian diet. Simply feeding these

An interesting example occurs in rabbits, which

levels of low-density lipoproteins.

extent, eating excess cholesterol may also raise plasma

the daily diet, obesity, and physical inactivity. To a lesser

several factors, including eating highly saturated fat in

lipoproteins. The plasma concentration of these high-

The Roles of Cholesterol

Basic Causes of Atherosclerosis

also the kidneys, liver, gastrointestinal tract, limbs, and

of the body, especially the brain (causing strokes), but

coronary arteries. The remaining one third are caused

Europe are due to vascular disease. About two thirds of

ow in the artery.

bus or embolus formation (see Chapter 36), leading to

can cause blood clots to develop, with resultant throm-

owing blood, their rough surfaces

walls, they are easily ruptured. Also, where the plaques

bility, and because of the degenerative areas in their

arteries.

Metabolism and Temperature Regulation

850

Unit XIII

later stages of the disease are called “hardening of the

”

Atherosclerotic arteries lose most of their distensi-

protrude into the fl

a sudden blockage of all blood fl

Almost half of all deaths in the United States and

these deaths are caused by thrombosis of one or more

by thrombosis or hemorrhage of vessels in other organs

so forth.

—

and Lipoproteins

Increased Low-Density Lipoproteins.

An important factor

in causing atherosclerosis is a high blood plasma con-
centration of cholesterol in the form of low-density

cholesterol low-density lipoproteins is increased by

normally have low plasma cholesterol concentrations

animals large quantities of cholesterol as part of their
daily diet leads to serious atherosclerotic plaques

Familial Hypercholesterolemia.

the person inherits defective genes for the formation of
low-density lipoprotein receptors on the membrane sur-
faces of the body’

cholesterol machinery of the liver cells goes on a

responsive to the feedback inhibition of too much

density lipoproteins released by the liver into the

Patients with full-blown familial hypercholes-

terolemia have blood cholesterol concentrations of 600

Many of these people die before age 20 because of
myocardial infarction or other sequelae of atheroscle-

Role of High-Density Lipoproteins in Preventing Atherosclerosis.

Much less is known about the function of high-density
lipoproteins compared with that of low-density lipopro-

actually absorb cholesterol crystals that are beginning

ratio of

of developing atherosclerosis is greatly reduced.

Other Major Risk Factors
for Atherosclerosis

In some people with perfectly normal levels of choles-

Some of the factors that are known to predispose to ath-
erosclerosis are (1) physical inactivity and

(2)

(3) hypertension, (4) hyperlipidemia,

atherosclerotic coronary artery disease by at least

that these factors interact in a synergistic manner to

to develop atherosclerosis than are women of compa-

Some of these factors cause atherosclerosis by

increasing the concentration of low-density lipoproteins

atherosclerosis by causing damage to the vascular en-
dothelium and other changes in the vascular tissues that
predispose to cholesterol deposition.

mental studies suggest that excess blood levels of iron

one quarter of all people have a special type of low-

additional protein, apoprotein(a), that almost doubles

nisms of these atherogenic effects have yet to be
discovered.

development of atherosclerosis and its progression to
serious vascular disease are (1) maintaining a healthy

contains mainly unsaturated fat with a low cholesterol

controlling blood pressure with antihypertensive drugs

blood glucose with insulin treatment or other drugs if

Several types of drugs that lower plasma lipids and

cholesterol have proved to be valuable in preventing

liver is converted into bile acids and secreted in this

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Ruderman NB, Saha AK, Kraegen EW: Malonyl CoA, AMP-

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ity from atherosclerotic heart disease. Therefore, appro-

plasma, there is about a 2 per cent decrease in mortal-

In general, studies show that for each 1 mg/dl

who have increased plasma cholesterol levels.

tion. These drugs are now widely used to treat patients

atherosclerosis, such as attenuating vascular in

in plasma levels of low-density lipoproteins. The statins

the liver, usually causing a 25 to 50 per cent reduction

of cholesterol. This inhibition decreases cholesterol syn-

, a rate-limiting enzyme in the synthesis

hydroxymethylglutaryl-coenzyme A (HMG-

tion, thereby reducing cholesterol synthesis by the liver.

atherogenic plaques.

stituent of many breakfast cereals, increases the pro-

lesterol to be converted into new bile acids. Thus, simply

circulating blood. This causes far more of the liver cho-

and used over and over again in the bile. Therefore, any

form into the duodenum; then, more than 90 per cent of

Chapter 68

Lipid Metabolism

851

these same bile acids is reabsorbed in the terminal ileum

agent that combines with the bile acids in the gastroin-
testinal tract and prevents their reabsorption into the
circulation can decrease the total bile acid pool in the

eating oat bran, which binds bile acids and is a con-

portion of liver cholesterol that forms new bile acids
rather than forming new low-density lipoproteins and

Resin agents can also be used to

bind bile acids in the gut and increase their fecal excre-

Another group of drugs called statins competitively

inhibits
CoA) reductase

thesis and increases low-density lipoprotein receptors in

may also have other beneficial effects that help prevent

flamma-

decrease in low-density lipoprotein cholesterol in the

priate preventive measures are valuable in decreasing

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flammatory

tion between carbohydrate and lipid oxidation during