Lipid Theory

D Kritchevsky, Wistar Institute, Philadelphia, PA, USA

© 2005 Elsevier Ltd. All rights reserved.


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 and tumor necrosis factors a and /3, among others. Monocytes 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


Size (nm)

Mol. wt




Major apoproteins


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