Lipid Theory

D Kritchevsky, Wistar Institute, Philadelphia, PA, USA

© 2005 Elsevier Ltd. All rights reserved.

Introduction

Arteriosclerosis is a group of conditions characterized by thickening and stiffening of the arterial wall. Atherosclerosis is characterized by the formation of ather-omas (lipid-laden plaques) in medium to large arteries. These are associated with calcifications of the arterial wall along with other changes. Eventually, the arterial lumen is reduced and the restricted blood flow due to these changes leads to clinical symptoms. Over the years there have been varying theories about the development of arterial lesions and these theories become more complex as our biochemical and molecular biological skills and knowledge increase.

Arterial fatty streaks are ubiquitous in humans and appear early in life. The fatty streak is comprised of lipid-rich macrophages and smooth muscle cells. Macrophages that accumulate lipid and are transformed into foam cells may be involved in the transformation of the fatty streak to an atherosclerotic lesion. In susceptible persons the fatty streaks may progress to fibrous plaques. Fibrous plaques, at their core, consist of a mixture of cholesterol-rich smooth muscle and foam cells. This core may contain cellular debris, cholesteryl esters, cholesterol crystals, and calcium. The fibrous cap consists of smooth muscle and foam cells, collagen, and lipid. The final stage in this process is the complicated plaque, which can obstruct the arterial lumen. Rupture of the cap may lead to clot formation and occlusion of the artery.

There are several theories of atherogenesis and these may eventually be shown to be interactive. The lipid hypothesis suggests that persistent hyperli-pidemia leads to cholesterol accumulation in the arterial endothelium. Hypercholesterolemia may activate protein growth factors, which stimulate smooth muscle cell proliferation.

The lipid infiltration hypothesis proposes that elevated LDL levels increase LDL infiltration which, in turn, increases uptake of epithelial cells, smooth muscle cells, and macrophages. This cascade leads to cholesterol accumulation and, eventually, atheroma formation. The endothelial injury may arise from the action of oxidized lipid.

The endothelial injury hypothesis may help to explain the focal distribution of atheromas, which is not adequately accounted for by the lipid hypothesis. The endothelial injury hypothesis asserts that plaque formation begins when the endothelial cells that cover fatty streaks separate thus exposing the underlying lesion to the circulation. This may lead to smooth muscle proliferation, stimulated by circulating mitogens, or may cause platelet aggregation leading to mural thrombosis.

Another hypothesis relating to atherogenesis is the response-to-injury hypothesis. In this hypothesis the injury may be due to mechanical factors, chronic hypercholesterolemia, toxins, viruses, or immune reactions: these increase endothelial permeability, and lead to monocyte adherence to the epithelium or infiltration and platelet aggregation or adherence at the site of the injury. Injury releases growth factors that stimulate proliferation of fibrous elements in the intima. These growth factors may arise from the endothelial cell, monocyte, macrophages, platelet, smooth muscle cell, and T cell. They include epidermal growth factor, insulin-like growth factors, inter-leukins 1 and 2, platelet-derived growth factors, transforming growth factors a and ft, and tumor necrosis factors a and ft, among others. Mono-cytes and smooth muscle cells carry the 'scavenger' receptor, which binds oxidized but not native low-density lipoprotein (LDL) in a nonsaturable fashion. Uptake of oxidized LDL converts macrophages and smooth muscle cells into foam cells. Another theory of atherogenesis suggests that it begins as an immunological disease, which starts by an autoimmune reaction against the heat stress protein, hsp60. There have been suggestions that oxidized LDL may be an underlying cause of arterial injury.

The term 'atherosclerosis' is derived from the Greek words athere, meaning gruel, and skleros, meaning hardening. The term was coined by Marchand in 1904 to describe the ongoing process beginning with the early lipid deposits in the arteries to the eventual hardening. The World Health Organization (WHO) definition describes atherosclerosis as a 'variable combination of changes in the intima of the arteries involving focal accumulation of lipids and complex carbohydrates with blood and its constituents accompanied by fibrous tissue formation, calcification, and associated changes in the media' - a decidedly more complex concept than attributing it all to the dietary cholesterol.

Discussions of the etiology of heart disease always describe it as a life-style disease and list a number of risk factors, which include family history, hypercholesterolemia, hypertension, obesity, and cigarette smoking. Having listed these factors, discussion generally reverts to blood cholesterol and its control.

Figure 1 Outline of lipid metabolism. Letters in parentheses refer to apolipoproteins (apo). HDL, high-density lipoprotein; VLDL, very-low-density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein.

The fasting blood plasma of a healthy individual is a clear, straw-colored liquid, which may contain 400-800 mg of lipids per 100 ml. This clear solution, which is high in lipids, is made possible by the water-soluble complex of lipids with protein, the lipoproteins. A generalized view of lipoprotein metabolism is provided in Figure 1. The existence of soluble lipid-protein complexes in serum was suggested about a century ago. Precipitation of a lipoprotein from horse serum was achieved in 1929 and classes of lipoproteins were adduced from studies using moving boundary electrophoresis. The critical experiments were carried out by Gofman and his group in the 1950s. They demonstrated that classes of lipoprotein complexes could be identified by their flotation characteristics in the analytical ultracentrifuge. These complexes were separable because they possessed different hydrated densities and they were defined initially by Svedberg units of flotation (Sf). The lipoproteins vary in chemical composition and although it is common to provide tables describing lipoprotein composition, the values are generally average values. This is so since the lipoproteins exist in a dynamic state exchanging their lipid components with those of tissues or other lipoproteins. Since identification is made according to a physical property, i.e., hydrated density, it is evident that different agglomerates of lipid and protein may have similar hydrated densities. In general, the lipoproteins are a series of macromolecules that, as they progress from low to high density, display decreasing triacylgly-cerol content and increasing cholesteryl ester, phospholipid, and protein.

Table 1 describes the major lipoproteins. Their chemical composition is described in Table 2.

As research continues and as analytical methodology becomes more precise we find a higher resolution of some lipoprotein classes and better definition of their roles. One example is lipoprotein (a) (lp(a)), first described in 1963. Lipoprotein (a) is an LDL whose normal apoprotein (apo B) is linked to an additional protein, apoprotein a, via a disulfide bridge. Lipoprotein (a) interferes with normal fibrinolysis leading to an increased prevalence of blood clots, and is thought to present an especially high risk for myocardial infarction. Characteristics and functions of lipoproteins are described in Table 3.

Molecular size influences the ease with which LDL particles can enter the arterial wall. Diabetic rabbits have greatly elevated plasma lipid levels but display surprisingly little atherosclerosis. The reason

Table 1 Major plasma lipoproteins

Lipoprotein

Size (nm)

Mol. wt

Density

Electrophoretic

Origin

Major apoproteins

class

(gml-1)

mobility

Chylomicron

100-400

106-107

<0.95

Origin

Intestine

A-I, B-48, C-II, C-III, E

VLDL

40-70

5 x 103

0.95-1.006

Prebeta

Liver

B-100, C-II, C-III, E

IDL

30-40

4.5 x 103

1.006-1.019

Between prebeta

Catabolism of VLDL

B-100, C-II, C-III, E

and beta

LDL

22.5-27.5

2 x 103

1.019-1.063

Beta

Catabolism of VLDL and IDL

B-100

HDL

7.5-10

0.4 x 103

1.063-1.210

Alpha

Liver, intestine

A-I, A-II, C-II, C-III, E

VLDL, very-low-density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; HDL, high-density lipoprotein.

VLDL, very-low-density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; HDL, high-density lipoprotein.

Table 2 Plasma lipoprotein composition

Lipoprotein Composition (wt%)

Table 2 Plasma lipoprotein composition

Lipoprotein Composition (wt%)

FC

CE

TAG

PL

PROT

Chylomicron

1

3

90

4

2

VLDL

7

14

55

16

8

IDL

6

22

30

24

18

LDL

7

48

5

20

20

HDL

4

15

4

27

50

FC, free cholesterol; CE, cholesteryl ester; TAG, triacylglycerol; PL, phospholipid; PROT, protein; VLDL, very-low-density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; HDL, high-density lipoprotein.

FC, free cholesterol; CE, cholesteryl ester; TAG, triacylglycerol; PL, phospholipid; PROT, protein; VLDL, very-low-density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; HDL, high-density lipoprotein.

for this apparent discrepancy is that the lipoproteins of diabetic rabbits are rather large in size and do not penetrate the artery. Since 1982 we have known of an array of LDL particles ranging from small and dense to large and comparatively light. An LDL pattern characterized by an excess of small, dense particles is associated with a threefold increased risk of myocardial infarction, independent of age, sex, or body weight. Commonly, LDL is known as the 'bad' cholesterol and high-density lipoprotein (HDL) as the 'good' cholesterol. These recent findings indicate the presence of 'good, bad' cholesterol and 'bad, good' cholesterol.

Among the apolipoproteins, polymorphism of apoprotein E apparently dictates a subject's chances for successful treatment of lipidemia. The apoE alleles are designated as E2, E3, and E4. The most common pattern (55%) is homozygosity for E3, which gives rise to the E3/E3 phenotype. The next most common phenotype is E3/E4 (26%). The least frequently observed phenotype is E2/E (1%), which is often associated with type III hyperlipoproteinemia. There is some evidence suggesting that subjects bearing the E4 allele have higher levels of LDL than those with the E3/E3 pattern; they may also be more prone to Alzheimer's disease. Tables 4 and 5 list primary and secondary dyslipoproteinemias.

Cholesterol and Cholesterolemia

In 1913 Anitschkow showed that it was possible to establish atherosclerosis in rabbits by feeding cholesterol. Since then virtually all research on atherosclerosis has centered on cholesterol -circulating cholesterol and dietary cholesterol. The epidemiological data suggest a role for

Table 3 Characteristics and functions of major apolipoproteins

Apolipoprotein

Lipoprotein

(Approximate molecular weight (kD))

concentration

(mgdL-1)

(Physiologic) function

A-1

HDL, chylomicrons

28

Liver, intestine

100-120

Structural apoprotein of HDL, cofactor for LCAT

A-II

HDL, chylomicrons

17

Intestine, liver

35-45

Structural apoprotein of HDL, cofactor for hepatic lipase

A-IV

HDL, chylomicrons

46

Liver, intestine

10-20

Unknown

Apo (a)

Lp(a)

600

Liver

1-10

Unknown

B-48

Chylomicrons

264

Intestine

Trace

Major structural apoprotein, secretion and clearance of chlylomicrons

B-100

VLDL, LDL

550

Liver

100-125

Ligand for LDL receptor, structural apoprotein of VLDL and LDL

C-I

Chylomicrons, VLDL, HDL

5.80

Liver

6-8

Cofactor for LCAT

C-II

Chylomicrons, VLDL, HDL

9.10

Liver

3-5

Cofactor for LCAT

C-III

Chylomicrons, VLDL, HDL

8.75

Liver

12-15

Inhibitor of LPL, involved in lipoprotein remnant uptake

E-2

Chylomicrons, VLDL, HDL

35

Liver, peripheral tissues

4-5

Ligand for cell receptor

E-3

Chylomicrons, VLDL, HDL

35

Liver, peripheral tissues

4-5

Ligand for cell receptor

E-4

Chylomicrons, VLDL, HDL

35

Liver, peripheral tissues

4-5

Ligand for cell receptor

HDL, LDL, VLDL, high-, low-, and very-low-density lipoprotein; LCAT, lecithin-cholesterol acyltransferase; LPL, lipoprotein lipase.

HDL, LDL, VLDL, high-, low-, and very-low-density lipoprotein; LCAT, lecithin-cholesterol acyltransferase; LPL, lipoprotein lipase.

Table 4 The primary dyslipoproteinemias

Type

Changes in plasma

Apparent genetic disorder

Biochemical defect

Lipids

Lipoproteins

I

TAG "

CM "

Familial LPL deficiency

Loss of LPL activity

II-a

C "

LDL "

Familial hypercholesterolemia

Deficiency of LDL receptor and

activity

II-b

C ", TAG "

LDL, VLDL "

Familial combined

Unknown

hyperlipidemia

III

C ", TAG "

ß-VLDL "

Familial type III hyperlipidemia

Defect in TAG-rich remnant

clearance

IV

TAG "

VLDL "

Familial hypertriacylglycerolemia

VLDL synthesis ", catabolism #

V

TAG ", C "

VLDL ", CM "

Familial type V

Lipolysis of TGA-rich LP #,

hyperlipoproteinemia

Production of VLDL TAG "

Hyper Lp(a)

C "

Lp(a) "

Familial hyper apo(a)

Inhibits fibrinolysis

lipoproteinemia

Hyperapobeta-

TAG "

VLDL, LDL "

Familial type V

CETP deficiency

lipoproteinemia

hyperlipoproteinemia

Familial hypobeta-

C #, TAG #

CM #, VLDL ",

?

Inability to synthesize apo B-48

lipoproteinemia

LDL #

and apo B-100

A-beta-lipoproteinemia

C #, TAG #

CM #, VLDL #,

?

Apo B-48 and apo B-100 not

LDL #

secreted into plasma

Hypo-alphalipoproteinemia

C #, TAG #

HDL #

?

LCAT deficiency

Tangier disease

ApoA-I #, apo C-III #

Fish eye disease

Abnormal apo A-I, and apo A-II

metabolism

C, cholesterol; CM, chylomicrons; CETP, cholesteryl ester transfer protein; HDL, LDL, VLDL, high-, low-, and very-low-density lipoprotein; LCAT, lecithin-cholesterol acyltransferase; LPL, lipoprotein lipase; TAG, triacylglycerol.

dietary fat, and hypercholesterolemia has been established as a principal risk factor for atherosclerosis. The lipid hypothesis was developed from the data obtained in the Framingham study, which suggested a curvilinear relationship between risk of atherosclerosis and plasma or serum cholesterol levels. However, studies of actual cholesterol intake as it affects cholesterol levels have yielded equivocal results.

Several studies have shown that the addition of one or two eggs to their daily diet did not influence serum cholesterol levels of free-living subjects. Data from the Framingham study show no correlation between cholesterol intake and cholesterol level. So we are left with the anomalous situation that blood cholesterol is an indicator of susceptibility to coronary disease but it is relatively unaffected by dietary cholesterol. It is of interest to point out that we are also seeing a correlation between low plasma or serum cholesterol levels and noncoronary death.

The type of fat in the diet has a strong influence on serum or plasma cholesterol levels. Rabbits fed saturated fat develop more severe atherosclerosis

Table 5

Secondary dyslipoproteinemias

Type

Associated disease

Lipoproteins elevated

Apparent underlying defect

I

Lupus erythematosis

Chylomicrons

Circulating LPL inhibitor

II

Nephrotic syndrome, Cushing's syndrome

VLDL and LDL

Overproduction of VLDL particles,

defective lipolysis of VLDL triglycerides

III

Hypothyroidism, dysglobulinemia

VLDL and LDL

Suppression of LDL receptor activity,

overproduction of VLDL triglycerides

IV

Renal failure, diabetes mellitus, acute hepatitis

VLDL

Defective lipolysis of triglyceride-rich

VLDL due to inhibition of LPL and HL

V

Noninsulin dependent diabetes

VLDL

Overproduction and defective lipolysis of

VLDL triglycerides

HDL, LDL, VLDL, high-, low, and very-low-density lipoprotein; HL, hepatic lipase; LPL, lipoprotein lipase.

HDL, LDL, VLDL, high-, low, and very-low-density lipoprotein; HL, hepatic lipase; LPL, lipoprotein lipase.

than do rabbits fed unsaturated fat. In 1965 the groups of Keys and Hegsted independently developed formulae for predicting changes in cholesterol levels based on changes in the diet. Their formulae were based upon changes in quantity of saturated and unsaturated fat and in dietary cholesterol, but the last value makes a very small contribution to the overall number. The Keys formula is:

where AC represents the change in cholesterol level, AS and AP represent changes in levels of saturated and unsaturated fat, and Z is the square root of dietary cholesterol in mg per 1000 kcal of diet. The Hegsted formula is:

where ACP is change in plasma cholesterol and ACD is change in dietary cholesterol in mg per 1000 kcal.

Both studies found that changes in dietary stearic acid did not fit the formula. Since those formulae were introduced a number of newer formulae have appeared, which provide a coefficient for every individual fatty acid, but the original formulae are still used most frequently. Under metabolic ward conditions it has been shown that lauric (C12:0), myristic (C14:0), and palmitic (C16:0) acids raise both LDL and HDL cholesterol levels, and that oleic (C18:1) and linoleic (C18:2) acids raise HDL and lower LDL levels slightly. Thus, the type of fat is the determining factor in considering dietary fat effects on serum cholesterol. Experiments in which subjects were fed low or high levels of cholesterol in diets containing high or low ratios of saturated to polyunsaturated fat have been reported. When the fat was homologous, changing from low to high dietary cholesterol raised serum cholesterol concentration by 2%. However, even under conditions in which low levels of cholesterol were fed, changing from saturated to unsaturated fat raised serum cholesterol levels by 10% or more.

In nature most, but not all, unsaturated fatty acids are in the cis configuration. The major source of fats containing trans unsaturated fatty acids (trans fats) in the diet of developed nations is hydrogenated fat, such as is present in commercial margarines and cooking fats. Interest in trans fat effects on atherosclerosis and cholesterolemia was first evinced in the 1960s. In general, trans fats behave like saturated fats and raise serum cholesterol levels, but have not been found to be more atherogenic than saturated fats in studies carried out in rabbits, monkeys, and swine. Studies have also shown that trans fat effects may be relatively small if the diet contains sufficient quantities of essential fatty acids.

Studies, clinical and epidemiological, on the influence of trans unsaturated fats on the risk of coronary heart disease have continued. The evidence is that trans fats may influence the chemical indicators of heart disease risk but final proof must rest on verification by clinical trial. The concerns relative to trans fat effects have led to recommendations that the levels of trans fats present in the diet be reduced as much as possible. The availability of trans-free margarines and other fats may render the entire argument obsolete.

Protein

The type of protein in the diet also influences cho-lesterolemia and atherosclerosis. In animal studies in which the sole source of protein is of animal or plant origin, the former is more cholesterolemic than atherogenic. However, a 1:1 mix of animal and plant protein provides the higher-grade protein of animal protein and the normocholesterolemic effects of plant protein. The results underline the need for a balanced diet.

Fiber

Dietary fiber may influence lipidemia and atherosclerosis. Substances designated as insoluble fibers (wheat bran, for instance) possess laxative properties but have little effect on serum lipid levels. Soluble fibers (gel-forming fibers such as pectin or guar gum) influence lipidemia and glycemia. Oat bran, which contains /3-glucans, which are soluble fibers, will lower cholesterol levels despite its designation.

Variations in Cholesterol Levels

Ignoring the differences of technique involved in cholesterol measurement in the laboratory - variations that are amenable to resolution - there are physiological considerations that should be recognized. Age, gender, genetics, adiposity, and personality traits can affect cholesterol levels, as can diseases unrelated to coronary disease. Stress (job stress, deadlines, examinations) can lead to increased cholesterol levels.

A definite seasonal variation in cholesterol levels (usually higher in winter months) has been seen in a number of studies. Scientists from the National Institutes of Health in the US carried out one of

Fibrous plaque

Figure 2 Factors involved in formation of the atherosclerotic plaque.

Foam cells

Fatty streak

Fibrous plaque

Figure 2 Factors involved in formation of the atherosclerotic plaque.

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