Caballero B. (ed.) Encyclopaedia of Food Science, Food Technology and Nutrition. Ten-Volume Set

Подождите немного. Документ загружается.

0037 The bile acid sequestrants bind bile acids in the

intestine promoting their excretion in the stool. This

interferes with the reabsorption of the bile acids,

causing more cholesterol to be converted into bile

acids in the liver. The hepatic cholesterol level falls,

and LDL receptors are induced, causing a fall in the

blood LDL cholesterol levels.

0038 Niacin is vitamin B

and is present in food at an

average level of about 50 mg per day. When niacin is

given in amounts 20- to 40-fold as much as this, it can

decrease FFA mobilization, leading to a decrease in

lipid in the liver, increased proteolysis of apoB-100,

and decreased VLDL production. Thus, both the

triacylglycerol-rich VLDL, and the product of VLDL

catabolism, the cholesterol-enriched LDL, fall as the

result of niacin treatment. Niacin has a separate effect

on raising HDL cholesterol, presumably by decreas-

ing the catabolism of HDL and its major apolipopro-

tein, apoA-1, in the liver. Niacin can be given as a

regular short-acting preparation or in an extended or

sustained release preparation.

0039 Fibric acid derivatives, such as gemfibrozil and

fenofibrate, are often used as drugs of choice for

marked triacylglycerol elevations. They act by induc-

ing the gene for LPL and repressing the gene for

apoC-3. This leads to an increased hydrolysis of

triacylglycerol by LPL and a decreased inhibition

of LPL by apoC-3.

0040 Combination therapy of HMG CoA inhibitors

with fibrates can cause a serious side-effect, called

myositis, which can lead to life-threatening rhabdo-

myolysis, and a specialist should carry out such

combined therapy.

0041 Knowledge of lipid disorders including abnormal-

ities in cholesterol metabolism and the consequences

of such has grown considerably, and many dyslipid-

emias are largely treatable with the proscribed means.

It is expected that in the 21st century, ASCVD will be

reduced considerably in developed countries, provid-

ing an increased quality of life and a prolonged life

span to humans. In addition, greater attention will

need to be paid to developing countries to prevent

them from assuming the rates of ASCVD in developed

nations.

See also: Cholesterol: Properties and Determination;

Factors Determining Blood Cholesterol Levels; Role of

Cholesterol in Heart Disease; Diabetes Mellitus:

Problems in Treatment; Secondary Complications; Fish

Oils: Composition and Properties; Dietary Importance;

Phospholipids: Properties and Occurrence;

Determination; Physiology; Stress and Nutrition;

Triglycerides: Structures and Properties;

Characterization and Determination; Vegetable Oils:

Composition and Analysis; Dietary Importance

Further Reading

Brown MS and Goldstein JL (1997) The SREBP pathway:

Regulation of cholesterol metabolism by proteolysis of

a membrane-bound transcription factor. Cell 89: 331–

340.

Cooper AD (1999) Role of the enterohepatic circulation of

bile salts in lipoprotein metabolism. Gastroenterology

Clinics of North America 28: 211–229.

Dietschy JM (1997) Theoretical considerations of what

regulates low-density-lipoprotein and high-density-lipo-

protein cholesterol. American Journal of Clinical Nutri-

tion 65: 158S–159S.

Dietschy JM (1998) Dietary fatty acids and the regulation

of plasma low density lipoprotein cholesterol concen-

trations. Journal of Nutrition 128 (Supplement 2):

444S–448S.

Grundy SM (1990) Cholesterol and atheriosclerosis. Diag-

nosis and treatment. Philadelphia, PA: JB Lippincott

Company; New York: Gower Medical Publishing.

Jones PJ (1997) Regulation of cholesterol biosynthesis by

diet in humans. American Journal of Clinical Nutrition

66: 438–446.

Kritchevsky D (1995) Dietary protein, cholesterol and

atherosclerosis: a review of the early history. Journal

of Nutrition 125 (Supplement 3): 589S–593S.

Kwiterovich PO (1998) The antiatherogenic role of high-

density lipoprotein cholesterol. American Journal of

Cardiology 82: 13Q–21Q.

National Cholesterol Education Panel (NCEP) (1993)

Adult treatment panel II. Journal of the American

Medical Association 269: 3015–3023.

tbl0006 Table 6 Characteristics of step one and step two diets for patients with dyslipidemias

Nutrient Step one diet Step two diet

Total fat (% of calories) Average of no more than 30 Same

Saturated fatty acids (%) <10 <7

Polyunsaturated fatty acids (%) Up to 10 Same

Monounsaturated fatty acids (%) Remaining total fat calories Same

Cholesterol (mg dl

1

) <300 <200

Carbohydrates (% of calories) About 55 Same

Proteins (% of calories) About 15–20 Same

From National Cholesterol Education Panel (NCEP) (1993) Adult treatment panel II. Journal of the American Medical Association 269: 3015–3023, with

permission.

1236 CHOLESTEROL/Absorption, Function, and Metabolism

Olson RE (1998) Discovery of the lipoproteins, their role

in fat transport and their significance as risk factors.

Journal of Nutrition 128 (Supplement 2): 439S–443S.

Ordovas JM (1999) The genetics of serum lipid responsive-

ness to dietary intervention. Proceedings of the Nutri-

tion Society 58: 171–187.

Rodriquez-Oquendo A and Kwiterovich PO. Jr. (2000) Dis-

orders of lipid and bile acid metabolism. In: Fernandes J,

Saudubray J-M and van den Berghe G (eds) Inborn

Metabolic Disease, 3rd edn. pp. 321–336. Berlin:

Springer.

Factors Determining Blood

Cholesterol Levels

S M Grundy, University of Texas, Dallas, TX, USA

Introduction

0001 A high blood (serum) cholesterol level is a major risk

factor for atherosclerotic coronary heart disease

(CHD). Consequently, there has been much interest

in the causes of elevated serum cholesterol concen-

trations. Although the serum cholesterol can be meas-

ured as a single entity, in fact cholesterol is carried in

the blood stream by several independent entities

called lipoproteins. Each lipoprotein has its own

characteristics and the concentrations of each are

affected by different factors. Several of these factors

are related to diet, i.e., dietary cholesterol, certain

fatty acids, and energy imbalance resulting in obesity.

Other factors also modify lipoprotein metabolism

including advancing age, the postmenopausal state

in women, and genetics. Consideration of each of

the factors regulating serum cholesterol concentra-

tions first requires a description of the different lipo-

protein species.

Serum Lipoproteins

0002 Lipoproteins are macromolecular complexes that

consist of discrete particles and are composed of

both lipids and proteins. The lipids include choles-

terol, phospholipids, and triacylglycerols (TAG). A

portion of serum cholesterol is esterified with a fatty

acid; the remainder is unesterified. The protein com-

ponents go by the name of apolipoproteins. The major

forms of apolipoproteins and their functions are

listed in Table 1. Four categories of lipoproteins that

carry cholesterol in the serum include chylomicrons,

very-low-density lipoproteins (VLDL), low-density

lipoproteins (LDL), and high-density lipoproteins

(HDL). The characteristics and metabolism of each

lipoprotein will be reviewed briefly.

Chylomicrons

0003Dietary cholesterol enters the intestine together with

fat, which is predominantly TAG. The latter under-

goes hydrolysis by pancreatic lipase and releases fatty

acids and monoacylglycerols. In the intestine, these

mix with bile acids, phospholipids, and cholesterol

from the bile. The mixture of hydrolyzed lipids

associates with phospholipids and bile acids to form

mixed micelles. Fatty acids, monoacylglycerols and

cholesterol are taken up by the intestinal mucosa. In

the mucosal cells, the fatty acids and monoacylglycer-

ols are recombined by enzymatic action to form TAG,

which are incorporated with the cholesterol into lipo-

protein particles called chylomicrons. Most of the

cholesterol in chylomicrons as esterified with a fatty

acid. The major apolipoprotein of chylomicrons is

apo B-48; other apolipoproteins – apo Cs, apo Es

and apo As – attach to the surface coat of chylomi-

crons and aid in metabolic processing. In the mucosal

cells, microsomal lipid transfer protein (MTP) facili-

tates the transfer of TAG and cholesterol ester

into chylomicron particles. The presence of MTP is

required for the secretion of chylomicrons from

mucosal cells.

0004Chylomicrons are secreted by intestinal mucosal

cells into the lymphatic system. From here they pass

through the thoracic duct into the systemic circula-

tion. When chylomicrons enter the peripheral circu-

lation they come into contact with an enzyme,

lipoprotein lipase (LPL), which is located on the

tbl0001Table 1 Apolipoproteins of serum lipoproteins

Apolipoprotein Function

A-I Major apolipoprotein of HDL

Activator of LCAT

A-I Structural apolipoprotein of HDL (other

functions unknown)

A-IV Apolipoprotein of chylomicrons (other

functions unknown)

B-48 Chylomicron assembly and secretion

B-100 VLDL assembly and secretion

Ligand for LDL receptor unknown

C-I Unknown

C-II Activator of LPL

C-III Inhibitor of LPL

E Apolipoprotein of remnant lipoproteins

Ligand for LDL receptor

Promotes hepatic uptake of remnants

HDL, high-density lipoproteins; LDL, low-density lipoproteins; VLDL, very-

low-density lipoproteins; LCAT, lecithin cholesterol acyl transferase; LPL,

lipoprotein lipase.

CHOLESTEROL/Factors Determining Blood Cholesterol Levels 1237

endothelial surface of capillaries. LPL is activated by

apo C-II on chylomicrons; this process is modulated

by apo C-III, an inhibitor of LPL activity. None the

less, most chylomicron TAG is hydrolyzed by LPL;

a residual lipoprotein particle, named chylomicron

remnant, is released into the circulation and is

rapidly removed by the liver. Hepatic uptake of chy-

lomicron remnants is believed to be mediated by

binding of remnants with a glycoprotein on the sur-

face of liver cells. Almost all newly absorbed choles-

terol thus enters the liver in association with

chylomicron remnants.

Very-Low-density Lipoproteins

0005 The liver also secretes a TAG-rich lipoprotein called

VLDL. Fatty acids used in the synthesis of TAG in

the liver are normally derived from circulating

nonesterified fatty acids (NEFA); even so, the liver

has the capacity to synthesize fatty acids when the

diet contains mainly carbohydrate. MTP inserts TAG

into newly forming VLDL particles. The surface coat

of VLDL contains unesterified cholesterol, phospho-

lipids and apolipoproteins. The major apolipoprotein

of VLDL is apo B-100. Other apolipoproteins,

notably apo Cs and apo Es, are also present. As

VLDL circulate they acquire cholesterol esters from

HDL. Circulating VLDL particles lose TAG through

interaction with LPL in the peripheral circulation; in

this process, VLDL are transformed into VLDL rem-

nants. The latter can have two fates: hepatic uptake

or conversion to LDL. Hepatic uptake of VLDL rem-

nants may occur via two mechanisms: interaction

with glycoproteins or interaction with LDL receptors.

Both glycoproteins and LDL receptors are located on

the surface of liver cells.

Low-density Lipoproteins

0006 Conversion of VLDL remnants to LDL appears to be

largely the result of hydrolysis of remaining TAG

by hepatic triacylglycerol lipase (HTGL). Normally

about two-thirds of cholesterol is carried by LDL;

most of this LDL cholesterol exists in the form of

esters. The only apolipoprotein in LDL is apo

B-100. LDL is removed from the circulation largely

by hepatic LDL receptors. The level of expression of

LDL receptors is a major determinant of serum LDL

cholesterol concentrations. The synthesis of LDL re-

ceptors is regulated in large part by the liver’s content

of cholesterol. An increase in hepatic cholesterol con-

tent suppresses LDL receptor synthesis and raises

serum LDL cholesterol; conversely, a decrease in

hepatic cholesterol stimulates receptor synthesis and

lowers serum LDL cholesterol. The mechanism

whereby hepatic cholesterol controls LDL receptor

synthesis is through a regulatory protein called sterol

regulatory element-binding protein (SREBP). When

hepatic cholesterol content falls, SREBP is activated

and stimulates the synthesis of LDL receptors.

0007The regulatory form of cholesterol in the liver cell

is unesterified cholesterol, not cholesterol ester. The

hepatic content of unesterified cholesterol depends on

several factors, including the amounts of cholesterol

derived from chylomicrons and other lipoproteins,

hepatic synthesis of cholesterol, secretion of choles-

terol into bile, conversion of cholesterol into bile

acids, esterification of cholesterol, and secretion of

cholesterol into serum with VLDL. Factors that influ-

ence each of these processes can alter serum LDL

cholesterol concentrations by modifying the hepatic

content of unesterified cholesterol and thereby

expression of LDL receptors.

High-density Lipoproteins

0008HDL consist of a series of lipoprotein particles of

relatively high density, all of which contain apo A-I.

A proportion of HDL particles also contain apo A-II.

Some HDL species (HDL

) are more dense than

others (HDL

). HDL particles are composed largely

of byproducts of catabolism of TAG-rich lipopro-

teins. The surface coats of HDL particles contain

phospholipids and unesterified cholesterol, apo A-I

with or without apo A-II, and other apolipoproteins

(apo Cs and apo Es). Their particle cores consist

largely of cholesterol esters, although small amounts

of TAG are also present. The cholesterol esters of

HDL are formed by esterification with a fatty acid

through the action of an enzyme, lecithin cholesterol

acyl transferase (LCAT); the substrates for this

reaction derive from either unesterified cholesterol

released during lipolysis of TAG-rich lipoproteins or

from the surface of peripheral cells. After esterifica-

tion of cholesterol, the cholesterol esters of HDL are

then transferred back to TAG-rich lipoproteins and

eventually are removed by the liver through direct

uptake of remnant lipoproteins or LDL. Whether

whole HDL particles can be directly removed from

the circulation is uncertain. Some investigators

believe that the HDL components are dismantled

and removed piecemeal.

Dietary Regulation of Serum Lipoproteins

0009A large body of research has shown that diet has

a major impact on the concentrations and compos-

ition of serum lipoproteins, and hence on serum

cholesterol concentrations. Three major factors

affect cholesterol and lipoprotein concentrations:

dietary cholesterol, the macronutrient composition

of the diet, particularly dietary fatty acids, and energy

1238 CHOLESTEROL/Factors Determining Blood Cholesterol Levels

balance, as reflected by body weight. The influence of

each of these factors can be considered.

Dietary Cholesterol

0010 All dietary cholesterol is derived from animal prod-

ucts. The major sources of cholesterol in the diet are

egg yolks, products containing milk fat, animal fats,

and animal meats. Many studies have shown that

high intakes of cholesterol will increase the serum

cholesterol concentration. Most of this increase

occurs in the LDL cholesterol fraction. When choles-

terol is ingested, it is incorporated into chylomicrons

and makes its way to the liver with chylomicron

remnants. There it raises hepatic cholesterol content

and suppresses LDL receptor expression. The result is

a rise in serum LDL cholesterol concentrations.

Excess cholesterol entering the liver is removed from

the liver either by direct secretion into bile or by

conversion into bile acids; also, dietary cholesterol

suppresses hepatic cholesterol synthesis. There is con-

siderable variability in each of these steps in hepatic

cholesterol metabolism; for this reason the quantita-

tive effects of dietary cholesterol on serum LDL chol-

esterol levels vary from one person to another. For

every 200 mg of cholesterol per day in the diet, serum

LDL cholesterol is increased on average by about

6mgdl

1

(0.155 mmol l

1

Macronutrient Composition of the Diet

0011 Dietary fat and fatty acids Most of the fat in the diet

consists of TAG that are composed of three fatty-acid

molecules bonded to glycerol. The contribution of

TAG to total energy intake varies among individuals

and populations, ranging from 15% to 40% of total

nutrient energy. The fatty acids of TAGs are of several

types: saturated, cis-monounsaturated, trans-mono-

unsaturated, and polyunsaturated fatty acids. All

fatty acids affect lipoprotein levels in one way or

another. Table 2 lists the major fatty acids of the

diet and denotes their effects on serum lipoproteins.

Also shown are the effects of carbohydrates, which

also influence serum lipoprotein metabolism. It

should be noted that all lipoprotein responses are

compared and related to those of cis-monounsatu-

rated fatty acids which are widely accepted to be

neutral, or baseline.

0012Saturated fatty acids The saturated fatty acids are

derived from both animal fats and plant oils. Rich

sources of dietary saturated fatty acids include butter

fat, meat fat, and tropical oils (palm oil, coconut oil,

and palm kernel oil). Saturated fatty acids are

straight-chain organic acids with an even number of

carbon atoms (Table 2). All saturated fatty acids that

have from eight to 16 carbon atoms raise the serum

LDL cholesterol concentration when they are con-

sumed in the diet. In the USA and much of Europe,

saturated fatty acids make up 12–15% of total

nutrient energy intake.

0013The mechanisms whereby saturated fatty acids raise

LDL cholesterol levels are not known, although avail-

able data suggest that they suppress the expression of

LDL receptors. The predominant saturated fatty acid

in most diets is palmitic acid (C

16:0

); it is cholesterol-

raising when compared with cis-monounsaturated

fatty acids, specifically oleic acid (C

18:cis1n-9

), which

tbl0002 Table 2 Macronutrient effects on serum lipoprotein cholesterol

Nutrient Symbol

VLDL cholesterol LDL cholesterol HDL cholesterol

Fatty acids

Saturated

Palmitic C

16:0

–

"" –

Myristic C

14:0

– """ #

Lauric C

12:0

– " –

Caproic C

10:0

– " –

Caprilic C

8:0

– " –

Stearic C

18:0

–––or#

trans-Monounsaturated trans C

18:1 n-9

– " or "" #

cis-Monounsaturated cis C

18:1 n-9

–––

Polyunsaturated

n-6

18:2 n-6

–or# –or# –or#

n-3

DHA, EPA ### –or# –

Carbohydrate """ – ##

First number denotes number of carbon atoms; second number denotes number of double bonds.

The dash (–) indicates that there is no change in level compared to that produced by cis-monosaturated fatty acids (oleic acid) (C

18:1 n-9

). All the

lipoprotein responses to oleic acid are considered ‘neutral’, i.e., no effect.

The letter ‘n’ and number indicate at which carbon atom, numbered from the terminal methyl group, the first double bond appears.

VLDL, very-low-density lipoproteins; LDL, low-density lipoproteins; HDL, high-density lipoproteins; DHA, docosahexanoic acid (C

22:6 n-3

); EPA,

eicosapentanoic acid (C

20:5 n-3

CHOLESTEROL/Factors Determining Blood Cholesterol Levels 1239

is considered to be ‘neutral’ with respect to serum

cholesterol concentrations. In other words, oleic

acid is considered by most investigators to have no

effect on serum cholesterol or lipoproteins. Another

saturated fatty acid, myristic acid (C

14:0

), apparently

raises LDL cholesterol concentrations somewhat

more than does palmitic acid, whereas other saturates

– lauric (C

12:0

), caproic (C

10:0

), and caprylic (C

8:0

)

acids – have a somewhat lesser cholesterol-raising

effect. On average, for every 1% of total energy con-

sumed as cholesterol-raising saturated, fatty acids,

compared with oleic acid, the serum LDL cholesterol

level is raised about 2 mg dl

1

(0.025 mmol l

1

0014 One saturated fatty acid, stearic acid (C

18:0

), does

not raise serum LDL cholesterol concentrations. The

main sources of this fatty acid are beef tallow and

cocoa butter. The reason for its failure to raise LDL

cholesterol concentrations is uncertain, but may be

the result of its rapid conversion into oleic acid in the

body.

0015 Trans-monounsaturated fatty acids These fatty

acids are produced by hydrogenation of vegetable

oils. Intakes of trans-monounsaturates vary from

one country to another depending on consumption

of hydrogenated oils. In many countries they contrib-

ute between 2% and 4% of total nutrient energy

intake. A series of trans acids are produced by

hydrogenation; most are monounsaturated. For

many years, it was accepted that trans-monounsatu-

rated fatty acids were neutral with respect to LDL

cholesterol concentrations. However, recent studies

have shown that they raise LDL cholesterol concen-

trations to a level similar to that of palmitic acid when

substituted for dietary oleic acid. In addition, they

cause a small reduction in serum HDL cholesterol

concentrations. Thus, trans-monounsaturates must

be placed in the category of cholesterol-raising fatty

acids.

0016 Cis-monounsaturated fatty acids The major fatty

acid in this category is oleic acid (C

18:cis1 n-9

). It is

found in both animal and vegetable fats, and typically

is the major fatty acid in diet. Intakes commonly vary

between 10% and 20% of total energy. Oleic acid

intake is particularly high in the Mediterranean

region where large amounts of olive oil are consumed.

Other sources rich in oleic acid are rapeseed oil

(canola oil) and high-oleic forms of safflower and

sunflower oils. Peanuts and pecans are also high in

oleic acid. Animal fats likewise contain a relatively

high percentage of oleic acid among all their fatty

acids; even so, these fats also tend to be rich in satur-

ated fatty acids. When high-carbohydrate diets are

consumed, the human body can synthesize fatty

acids; among these, oleic acid is the predominant

fatty acid produced.

0017As indicated before, oleic acid is generally con-

sidered to be the ‘baseline’ fatty acid with respect

to serum lipoproteins levels, i.e., it does not raise

(or lower) LDL cholesterol or VLDL cholesterol

concentrations, nor does it lower (or raise) HDL

cholesterol concentrations. It is against this ‘neutral’

fatty acid that responses of other fatty acids are de-

fined (Table 2). For example, when oleic acid is sub-

stituted for cholesterol-raising fatty acids, the serum

LDL cholesterol concentration will fall. None the

less, oleic acid is not designated a cholesterol-

lowering fatty acid, but instead, this response defines

the cholesterol-raising potential of saturated fatty

acids.

0018Polyunsaturated fatty acids There are two categor-

ies of polyunsaturated fatty acids: n-6 and n-3. The

major n-6 fatty acid is linoleic acid (C

18:2,n-6

). It is the

predominant fatty acid in many vegetable oils, e.g.,

corn oil, soya bean oil, and high linoleic forms of

safflower and sunflower seed oils. Intakes of linoleic

acid typically vary from 4 to 10% of nutrient energy,

depending on how much vegetable oil is consumed

in the diet. The n-3 fatty acids include linolenic acid

18:3,n-3

), docosahexanoic acid (DHA) (C

22:6,n-3

and eicosapentanoic acid (EPA) (C

20:5,n-3

). Linolenic

acid is high in linseed oil and present in smaller

amounts in other vegetable oils. DHA and EPA are

enriched in fish oils.

0019For many years, linoleic acid was thought to be a

unique LDL cholesterol-lowering fatty acid. Recent

investigations suggest that earlier findings overesti-

mated the LDL-lowering potential of linoleic acid.

Even though substitution of linoleic acid for oleic

acid in the diet may reduce LDL cholesterol levels in

some people, a difference in response is not consist-

ent. Only when intakes of linoleic acid become quite

high do any differences become apparent. At high

intakes, however, linoleic acid also lowers serum

HDL cholesterol concentrations. Moreover, com-

pared with oleic acid, it may reduce VLDL cholesterol

levels in some people. Earlier enthusiasm for high

intakes of linoleic acid to reduce LDL cholesterol

levels has been dampened for several reasons: for

example, its LDL-lowering ability does not offset

potential disadvantages of HDL lowering; and other

concerns include possible untoward side-effects such

as promoting oxidation of LDL and suppressing

cellular immunity to cancer.

0020The n-3 fatty acids in fish oils (DHA and EPA) have

a powerful action to reduce serum VLDL levels. This

action apparently results from suppression of the se-

cretion of VLDL by the liver. The precise mechanism

1240 CHOLESTEROL/Factors Determining Blood Cholesterol Levels

for this action is not known. However these fatty

acids do not reduce LDL cholesterol concentrations

relative to oleic acid. They have been used for one

treatment of some patients with elevated VLDL con-

centrations, although drug treatment is generally

employed when it is necessary to lower serum VLDL

levels.

0021 Carbohydrate When carbohydrates are substituted

for oleic acid in the diet, serum LDL cholesterol levels

remain unchanged. However, VLDL cholesterol con-

centrations usually rise and HDL cholesterol concen-

trations fall on high-carbohydrate diets. Thus, a lack

of difference in total serum cholesterol concentrations

during the exchange of carbohydrate and oleic acid is

misleading. The two categories of nutrients have dif-

ferent actions on lipoprotein metabolism. The differ-

ences in response to dietary carbohydrate and oleic

acid provide a good example of how measurements of

serum total cholesterol fail to reveal all of the changes

that are occurring in the lipoprotein fractions.

Energy Balance

0022 Obesity When energy intake exceeds energy ex-

penditure, the balance of energy is stored in adipose

tissue in the form of TAG. When the TAG content of

adipose tissue becomes excessive (body mass index 30

or above), a state of obesity is said to exist. In some

obese persons, excessive accumulations of TAG occur

in other tissues than adipose tissue. Two such tissues

are skeletal muscle and liver. High contents of TAG in

muscle and liver arise due in large part to continuous

leakage of excessive quantities of NEFA from adipose

tissue. In the presence of desirable body weight,

normal insulin levels are sufficient to suppress

hydrolysis of TAG in adipose tissue, and NEFA re-

lease is low. On the other hand, in obese persons

NEFA release is excessive and skeletal muscle and

liver are flooded with high serum NEFA concentra-

tions. The result is engorgement of these organs with

TAG. When skeletal muscle is overloaded with TAG,

insulin-mediated glucose uptake is impaired. This

condition is called insulin resistance. When liver is

packed with TAG, hepatic metabolism is altered and

insulin action on the liver is deranged. As a result,

there is an overproduction of VLDL; this leads to high

VLDL cholesterol concentrations, and because LDL

is a product of VLDL, to higher LDL cholesterol

levels. In addition, obesity is accompanied by a reduc-

tion in HDL cholesterol concentrations. Thus obesity

is responsible for multiple alterations in lipoprotein

metabolism; it has significant effects on three major

lipoprotein species – VLDL, LDL, and HDL. These

changes appear to be the result of a combination of

excessive hepatic TAG as a substrate for VLDL

formation and failure of insulin to exert its usual

action to curtail VLDL secretion.

0023Exercise Many of the adverse metabolic effects of

obesity are reversed by exercise. Increased energy

expenditure through regular and sustained exercise

helps to prevent accumulation of excessive quantities

of TAG in adipose tissue. In addition, increased

muscle metabolism produced by exercise burns off

NEFA and prevents TAG accumulation in the liver.

Hence, increased and sustained energy expenditure

favorably modifies the lipoproteins, particularly by

lowering VLDL cholesterol concentrations and rais-

ing serum HDL cholesterol. The effects of exercise on

LDL cholesterol concentrations are more modest, but

in some people exercise produces a reduction.

Other Factors Affecting Serum

Lipoproteins

Advancing Age

0024Between the ages of 20 and 50 years, there is a grad-

ual rise in serum cholesterol concentrations. In the

USA, for example, the serum cholesterol increases

on average about 50 mg dl

1

(1.295 mmol l

1

). This

change may be related in part to increasing obesity,

according to the mechanisms described above. How-

ever, even in people who do not gain weight with

advancing age, serum cholesterol concentrations usu-

ally rise to some extent. Available evidence indicates

that this rise results from a decrease in expression of

LDL receptors. The reasons for a decline in receptor

synthesis with aging are not known, but may reflect

‘metabolic’ aging. However, in men, after age 50

years, there is little further rise in serum cholesterol.

This observation suggests that the impact of weight

gain, which occurs mostly between the ages of 20 and

50 years, may be greater than generally recognized.

Postmenopausal State in Women

0025In women, there is a further rise in serum cholesterol

concentrations which occurs after age 50 years. This

rise is believed to be due largely to loss of estrogens

after the menopause. Estrogens are known to stimu-

late the synthesis of LDL receptors and, consequently,

receptor expression declines after the menopause.

This increment in cholesterol levels can be largely

reversed by estrogen replacement therapy.

Genetics

0026Family studies and research in twins indicate that

about 50% of the variation of serum cholesterol

concentrations in the general populations can be

explained by genetic polymorphisms. Presumably

CHOLESTEROL/Factors Determining Blood Cholesterol Levels 1241

this variation is related to factors that regulate lipo-

protein concentrations. In some cases, specific genetic

defects are severe, resulting in marked changes in

lipoprotein concentrations. When this occurs, the

affected individual is said to have a monogenic dis-

order. In other cases, multiple genetic modifications

are present that combine to alter lipoprotein concen-

trations. When a few modifications are present, the

condition is called oligogenic, but when many modi-

fications combine to change lipoprotein concentra-

tions, the condition is named polygenic. Several

monogenic disorders have been identified; a few oli-

gogenic conditions have been described; but there are

very few instances in which complex polygenic traits

have been unraveled. A question of great interest is

whether nutritional and genetic factors ever interact

synergistically to alter lipoprotein concentrations.

Undoubtedly, dietary factors and genetic changes

can be additive in their effects on serum lipoproteins;

but synergistic interaction has been difficult to prove.

In what follows, consideration will be given to the

impact of modification of some of the key gene prod-

ucts regulating lipoprotein metabolism.

0027 LDL Receptors The most severe elevations in LDL

cholesterol levels occur in patients who have muta-

tions in the gene encoding for LDL receptors. About

one in 500 people are heterozygous for these muta-

tions. Their condition is called heterozygous familial

hypercholesterolemia. LDL cholesterol concentra-

tions are essentially twice the normal level in this

condition. Very rarely patients are homozygous for

mutation in the LDL receptor gene, and thus have

homozygous familial hypercholesterolemia. Their

LDL cholesterol levels are approximately four times

normal. Individuals with this condition develop

severe, premature atherosclerosis.

0028 Many other people appear to have a reduction in

LDL receptor expression on a genetic basis, but they

do not have as severe elevations of serum LDL chol-

esterol as occur in patients with familial hypercholes-

terolemia. Presumably, these people have genetic

modifications in factors that regulate transcription

of the LDL receptor gene. Although such genetic

modifications may be relatively common, they are

poorly defined. Again, an important but unanswered

question is whether some people are genetically sus-

ceptible to the cholesterol-raising effects of dietary

cholesterol and saturated fatty acids. If so, they may

possess modifications in the genetic control of LDL

receptor expression.

0029 Apolipoprotein B-100 Structure About one in 500

people also have a mutation in the primary structure

of apo B that interferes with its binding to LDL

receptors. This mutation gives rise to the disorder

called familial defective apolipoprotein B-100. The

consequence is an elevation of LDL cholesterol con-

centrations, and the clinical pattern resembles that of

familial hypercholesterolemia.

0030Apolipoprotein B Synthesis Rare patients have mu-

tations in the gene encoding for apo B that impair the

synthesis of this apolipoprotein. Such patients usually

have very low LDL cholesterol concentrations. These

individuals are said to have familial hypobetalipo-

proteinemia. In other rare cases, the intracellular

TAG transport protein called MCT (medium chain

triglyceride) is genetically absent; when this occurs,

no lipoprotein particles containing apo B can be

formed. LDL cholesterol is absent from serum, and

the disorder is called familial abetalipoproteinemia.

0031Some researchers speculate that serum elevations in

VLDL cholesterol and LDL cholesterol can result from

excessive synthesis and/or secretion of apo B-contain-

ing lipoproteins by the liver. When this occurs on a

genetic basis, the disorder is designated familial com-

bined hyperlipidemia. However, a monogenic basis of

this clinical phenotype has never yet been identified.

Therefore, most investigators have concluded that fa-

milial combined hyperlipidemia most likely represents

an oligogenic or polygenic disorder. In this disorder,

lipoprotein elevations appear to be worsened by nutri-

tional factors, particularly by obesity.

0032Apolipoprotein E This apolipoprotein is present on

TAG-rich lipoproteins and it facilitates removal of

remnant lipoproteins by LDL receptors in the liver.

When apo E is affected by mutation, this enabling

action is curtailed and hepatic uptake of remnant

lipoproteins is impaired. The result is an accumula-

tion of chylomicron remnants and VLDL remnants in

the circulation. The accumulation is accentuated by

the coexistence of other disorders of metabolism of

TAG-rich lipoproteins. When remnant accumulation

occurs on a genetic basis, the disorder is called

familial dysbetalipoproteinemia.

0033Apolipoprotein C There are two forms of apo C –

apo C-II and apo C-III. Apo C-II is required for acti-

vation of LPL; when it is genetically absent, affected

patients develop severe elevations of TAG-rich lipo-

proteins. Apo C-III inhibits the activity of LPL. In

certain metabolic disorders, notably insulin resistance,

synthesis of apo C-III is increased; an elevated apo C-

III can lead to impaired function of LPL and increases

in serum concentrations of TAG-rich lipoproteins.

0034Apolipoprotein A-I This is the major apolipopro-

tein of HDL. Rare patients have mutations in apo

1242 CHOLESTEROL/Factors Determining Blood Cholesterol Levels

A-I which results in very low concentrations of HDL

cholesterol. However, most people in whom HDL

cholesterol concentrations are moderately reduced

show increased catabolism of apo A-I. The mechan-

ism for this change has not been fully determined, but

one important cause may be an overexpression of

HTGL.

0035 Lipoprotein Lipase This enzyme is required for lipo-

lysis of TAG in TAG-rich lipoproteins. Rare patients

are homozygous for mutations in LPL that impair its

function. In such patients, serum concentrations of

chylomicrons are markedly increased. The accumula-

tion of chylomicrons in serum is greatly accentuated

by the presence of fat in the diet. Only by severe

dietary fat restriction is it possible to prevent severe

TAG elevations in serum.

0036 Genetic Regulation of HDL Cholesterol Family and

twin studies reveal that about 50% of the variation in

serum HDL cholesterol levels in the general popula-

tion is explained by genetic factors. However, the

regulation of HDL cholesterol concentrations is com-

plex, and HDL cholesterol levels are determined by

many factors, e.g., serum TAG concentrations, activ-

ity of HTGL, production rates of apo A-I, and activ-

ities of cholesterol ester transfer protein (CETP) and

LCAT. Genetic factors undoubtedly affect each of

these regulating factors.

See also: Eggs: Dietary Importance; Exercise: Muscle;

Fatty Acids: Properties; Metabolism; Gamma-linolenic

Acid; Analysis; Dietary Importance; Tr a n s -fatty Acids:

Health Effects; Meat: Nutritional Value; Obesity: Etiology

and Diagnosis; Poultry: Chicken; Ducks and Geese;

Turkey

Further Reading

Bonanome A and Grundy SM (1988) Effect of dietary

stearic acid on plasma cholesterol and lipoprotein levels.

New England Journal of Medicine 318: 1244–1248.

Cater NB, Heller HJ and Denke MA (1997) Comparison of

the effects of medium-chaintriacylglycerols, palm oil, and

high oleic sunflower oil on plasma acylglycerol fatty acids

and lipid and lipoprotein concentrations in humans.

American Journal of Clinical Nutrition 65: 41–45.

Connor WE (1988) Effects of omega-3 fatty acids in hyper-

triglyceridemic states. Seminars in Thrombosis and

Hemostasis 14: 271–284.

Denke MA, Sempos CT and Grundy SM (1993) Excess

body weight: an underrecognized contributor to high

blood cholesterol levels in white American men. Arch-

ives of Internal Medicine 153: 1093–1103.

Dietschy JM, Turley SD and Spady DK (1993) Role of

liver in the maintenance of cholesterol and low density

lipoprotein homeostasis in different animal species,

including humans. Journal of Lipid Research 34:

1637–1659.

Ericsson S, Eriksson M, Vitols S, Einarsson K, Berglund L

and Angelin B (1991) Influence of age on the metabolism

of plasma low density lipoproteins in healthy males.

Journal of Clinical Investigation 87: 591–596.

Expert Panel on Detection, Evaluation, and Treatment of

High Blood Cholesterol in Adults (SM Grundy, chair-

man) (1994) National cholesterol education program:

second report of the expert panel on detection, evalu-

ation, and treatment of high blood cholesterol (adult

treatment panel II). Circulation 89: 1329–1445.

Grundy SM (1986) Comparison of monounsaturated fatty

acids and carbohydrates for lowering plasma choles-

terol. New England Journal of Medicine 314: 745–748.

Grundy SM (1991) Multifactorial etiology of hypercholes-

terolemia: implications for prevention of coronary

heart disease. Arteriosclerosis and Thrombosis 11:

1619–1635.

Grundy SM and Denke MA (1990) Dietary influences on

serum lipids and lipoproteins. Journal of Lipid Research

31: 1149–1172.

Hegsted DM, McGandy RB, Myers ML and Stare FJ (1965)

Quantitative effects of dietary fat on serum cholesterol

in man. American Journal of Clinical Nutrition 17:

281–295.

Innerarity TL, Mahley RW, Weisgraber KH et al. (1990)

Familial defective apolipoprotein B-100: a mutation of

apolipoprotein B that causes hypercholesterolemia.

Journal of Lipid Research 31: 1337–1349.

Keys A, Anderson JT and Grande F (1965) Serum choles-

terol response to changes in the diet. IV. Particular satur-

ated fatty acids in the diet. Metabolism 14: 776–787.

Mattson FH and Grundy SM (1985) Comparison of effects

of dietary saturated, monounsaturated, and polyunsat-

urated fatty acids on plasma lipids and lipoproteins in

man. Journal of Lipid Research 26: 194–202.

Mensink RP and Katan MB (1990) Effect of dietary trans

fatty acids on high-density and low-density lipoprotein

cholesterol levels in healthy subjects. New England Jour-

nal of Medicine 323: 439–445.

Role of Cholesterol in Heart

Disease

R M Shireman, University of Florida, Gainesville,

FL, USA

Background

0001The compound cholesterol (3b-cholest-5-en-3-ol)

O) (Figure 1) was first isolated from gall-

stones in the late eighteenth century. Its crystalline

structure has been determined by X-ray diffraction.

CHOLESTEROL/Role of Cholesterol in Heart Disease 1243

More Nobel prizes have been awarded to scientists

who worked on cholesterol synthesis, metabolism,

and function than on any other compound. Much of

the work on the complex biosynthetic pathway was

done in the 1950s by Konrad Bloch, Feodor Lynen,

John Cornforth, and George Popja

k, yet many ques-

tions remain unanswered. Vertebrates and most other

animals can synthesize cholesterol de novo. Similar

sterol compounds called phytosterols are synthesized

by the same pathway in plant cells. Cholesterol is

essential in all animal cells, and either too much or

too little is detrimental. A familiar example of choles-

terol accumulation occurs in the disease athero-

sclerois, in which build-up occurs in the lining of the

lumen of arteries. A less familiar example is Wolman’s

disease, a hereditary deficiency in an enzyme, choles-

teryl ester hydrolase, in which cholesterol esters

rapidly accumulate to very high levels in fetal cells,

with ensuing mental retardation and other problems,

leading to infantile death. Conversely, Smith–Laemli–

Opitz syndrome is characterized by an inherited

enzyme defect in the last step in cholesterol synthesis,

resulting in very low cholesterol levels in cells, severe

mental retardation, and abnormal skeletal develop-

ment. The major consequence of these enzyme defi-

ciencies that produce very high vs. very low

intracellular cholesterol is severe mental retardation;

this illustrates the importance of the strict regulation

of cholesterol concentrations in cells. Cholesterol is

present in high amounts in the brain and nervous

system; in fact, about a quarter of the body’s choles-

terol is present in myelin. Table 1 lists some of the

important functions of this sterol.

0002 It is estimated that the adult human body contains

about 100 g of cholesterol. The average adult requires

approximately 1.1 g of cholesterol per day. About 15–

25% of this is normally derived from the diet, while

the rest is from endogenous synthesis, mainly in the

liver and intestine. This explains why it is rather

difficult to reduce blood cholesterol levels to any

great extent by decreasing the intake of dietary

cholesterol. Cholesterol absorption varies widely

among individuals and also in the same individual,

depending on other constituents in the diet. Choles-

terol absorption is very high in about 20% of the

population; these individuals have been referred to

as ‘hyper-responders.’ Plant sterols are not absorbed

well, but they do decrease cholesterol absorption. A

number of factors have been reported to affect ab-

sorption besides phytosterols, including vitamin C,

several different metal ions, and various types of

protein or fiber, but there is little general agreement

about the real physiologic effects, if any, of these

agents. Unesterified cholesterol that enters the

enterocyte (intestinal cell) is esterified before packag-

ing into chylomicrons. Chylomicrons are large lipo-

protein particles assembled in enterocytes and

transported first in the lymph and then by the blood-

stream to the liver. If insufficient cholesterol is

absorbed to provide for the packaging of other

absorbed fats into chylomicrons, enterocytes synthe-

size the needed cholesterol. Cholesterol biosynthesis

is regulated somewhat differently in different cells,

but feedback inhibition of synthesis occurs in most

cells except enterocytes. The exact regulation of this

process in enterocytes is still unclear, but it is evident

that increased dietary fat absorption increases the

intestinal biosynthesis of cholesterol.

Cholesterol Metabolism

0003Cholesterol is not metabolized for energy. It is re-

moved from the body via desquamating cells and by

the excretion of cholesterol and its products, includ-

ing bile acids and steroid hormone catabolites. A

relatively constant level is maintained in the body by

controlling the rate of biosynthesis, rather than by

conversion to products. Although most cells are

capable of synthesizing cholesterol, the liver is re-

sponsible for much of the cholesterol subsequently

delivered to cells such as neurons. Important clues

to the synthesis of sterols came from the work of

CHCH

Cholesterol

fig0001 Figure 1 Structure of cholesterol.

tbl0001Table 1 Major functions of cholesterol

Function Comments

Membrane structure

and integrity

Structural and protective functions;

helps maintain the semipermeable

barrier; especially important in

myelin structure

Precursor to

steroid hormones

Required for synthesis of progesterone,

testosterone, estrogen,

corticosteroids, and aldosterone

Precursor to vitamin D Cholesterol in skin cells is converted

to a precursor form under the

influence of UV irradiation (sunlight)

Precursor to bile acids Cholesterol and bile acids are

emulsifiers in bile and aid in

digestion and absorption of dietary fat

1244 CHOLESTEROL/Role of Cholesterol in Heart Disease

Konrad Block in the early 1940s, when he fed

(U)[

C]acetate to rats and found all 27 carbons of

cholesterol to be derived from acetate. The discovery

that mevalonic acid is an intermediate allowed

great progress in defining this pathway, which has a

huge number of enzymatic steps. An abbreviated

pathway is shown in Figure 2. Several important

compounds in addition to cholesterol are synthesized

in this pathway, commonly called the isoprenoid

pathway.

0004 Numerous genetic factors, as well as levels of

hormones and nutrients, influence cholesterol

homeostasis. Although the isoprenoid pathway may

be controlled at several separate enzymatic steps, the

key regulatory enzyme is hydroxymethylglutaryl-

coenzyme A reductase (HMG-CoA). HMG-CoA

reductase is an endoplasmic reticulum enzyme subject

to a high degree of regulation by several and varied

means. The enzyme is regulated acutely in response to

extracellular signals through a cAMP-mediated phos-

phorylation cascade. Phosphorylation decreases the

activity of this enzyme. Longer-term control depends

on the regulation of transcription of the gene for

reductase. Sterol accumulation normally decreases

mRNA synthesis of reductase and may accelerate

reductase degradation. A sterol regulatory element

(SRE-1) is the recognition site for a specific DNA-

binding protein whose activity is influenced by intra-

cellular sterol levels. The SRE of the reductase gene

promoter shares homology with those of HMG-CoA

synthetase and low-density lipoprotein (LDL) recep-

tor, suggesting coordinate control of these pathways

by sterol effectors. Coordinate control of the three

proteins allows very fine regulation of this synthetic

pathway. Thus, when the intracellular concentrations

of cholesterol or oxysterol become elevated, de-

creased transcription of two major genes in the chol-

esterol biosynthetic pathway leads to a decline in

cholesterol biosynthesis by that cell, and decreased

transcription of the LDL receptor protein leads to a

decrease in cellular uptake of cholesterol via LDL.

Reductase synthesis and activity are influenced also

by hormones, especially insulin and glucagon.

0005The rate of synthesis of cholesterol is increased in

proliferating normal tissues and tumors. Inhibition of

cholesterol synthesis inhibits cell growth. In addition

to the needs for cholesterol, other compounds from

this pathway have important functions in dividing

cells. For example, the farnesyl moiety activates

some of the proteins involved in regulation of cell

growth, and farnesyl and other prenyl groups are

used in modifying certain membrane proteins. Inhib-

ition of HMG-CoA reductase can affect the synthesis

of all products of the isoprene pathway. A

large number of pharmacologic inhibitors, mostly

competitive inhibitors of reductase, are now on the

market. Obviously, cholesterol-lowering drugs that

inhibit reductase should be used with great caution

in growing children, and not at all during pregnancy.

In vitro studies have shown that compounds such as

the monounsaturated fatty acid oleic acid inhibit

reductase activity to some extent. Certain xenobiotic

compounds, such as phenobarbital, which induce

enzymes of the cytochrome P450 system, also affect

some of the enzymes of cholesterol metabolism.

Other enzymes affecting cholesterol metabolism are

Acetyl CoA

HMG CoA

Reductase inhibitors

Farnesylated proteins

Mevalonate

IPP

Geranyl-PP

Farnesyl-PP

Squalence

(Squalene synthetase)

Cholesterol Bile acids, steroid hormones, vitamin D

Ubiquinone, dolichol

Geranylated proteins

Isopentenyladenine

(HMG CoA Reductase)

(HMG CoA Synthase)

Isopentenyl-tRNA

fig0002 Figure 2 Major steps in the biosynthetic pathway for cholesterol. The major regulated enzymes are shown in italics.

CHOLESTEROL/Role of Cholesterol in Heart Disease 1245