Atherosclerosis plasma cholesterol , role

H33. Hopkins, G. J., and Barter, P. J., Role of esterified cholesterol transfers in the regulation of plasma cholesterol esterification. Atherosclerosis 49, 177-185 (1983). 

It seems unlikely, however, that variations in dietary fat intake can explain the geographical distribution of cardiovascular disease, and perhaps there has been too much emphasis on dietary fat in atherosclerosis research. Experiments in animals have provided evidence that non-lipid components of the diet can also influence the level of plasma cholesterol and may play a role in the development of atherosclerosis (Carroll Hamilton, 1975 Hamilton Car-roll, 1976 Carroll et al, 1976). More attention might profitably be devoted to investigating the possibility that non-lipid components of the diet have an important influence on cardiovascular disease in human populations. 

Elevation of plasma cholesterol, particularly low-density lipoprotein cholesterol (LDL-C), is positively correlated with coronary heart disease (CHD), a major vascular disease predominantly causing by atherosclerosis (1,2). Recent studies have indicated that LDL oxidation, endothelial dysfunction, and inflammation play important roles in the molecular pathogenesis of atherosclerosis (3). Oxidized LDL (OxLDL) appears in the circulation and tends to infiltrate into the aortic endothelium (4). Antioxidants, which inhibit LDL oxidative modification, may reduce early atherogenesis and slow down the disease progression to an advanced stage (5). 

Reviews of the literature reveal numerous studies on atherosclerosis are concerned with cholesterol, its presence in or absence from the diet, its synthesis and catabolism, and its distribution among plasma and various tissues. Epidemiological studies in man suggest that diet -high in fat or cholesterol along with fat - plays a prominent role in the human atherosclerotic disease. Cholesterol, linked to the disease by its presence in the atherosclerotic plaques and its effect in diets of animals, iS derived both from diet and by biosynthesis in body tissues. Rats and rabbits, so often used in laboratory studies, differ greatly in susceptibility to atherosclerosis and may well be quite different from humans in this respect. Even on semi-synthetic diets, containing no added cholesterol, rabbits develop atherosclerosis, whereas they do not on stock diets. Furthermore, the plasma cholesterol of rabbits is more easily altered than that of rats, whereas the cholesterol synthesis rate (from acetate) varies widely in rats in response to various diets. 

A high plasma concentration of LDL (usually measured as LDL-cholesterol) is a risk factor for the development of atheroma whereas a high concentration of HDL is an anti-risk factor for cardiovascular disease (CVD). Fundamental discoveries relating to cholesterol metabolism and the importance of the LDL receptor made by Nobel laureates Joseph Goldstein and Michael Brown led to an understanding of the role of LDL in atherosclerosis. The impact of HDL in reducing CVD risk is often explained by the removal of excess cholesterol from tissues and its return to the liver, a process known as reverse cholesterol transport. However, evidence from research by Gillian Cockerill and others shows that HDL has a fundamental anti-inflammatory role to play in cardioprotection. 

Hodis, H.N., Crawford, D.W., Sevanian, A. 1991. Cholesterol feeding increases plasma and aortic tissue cholesterol oxide levels in parallel further evidence for the role of cholesterol oxidation in atherosclerosis. Atheroscler. 89, 117-126. 

As the knowledge of the pathogenesis of atherosclerosis rapidly increases, it appears that an active vascular endothelium, smooth muscle cells, and blood-borne cells such as monocytes and macrophages all play active roles in the atherosclerotic disease process. Risk factors, such as elevated plasma levels of certain lipids, prooxidants, and cytokines, may contribute to the chronic activation/stimulation as well as to the damage of the endothelium and other vascular tissues (160). There is evidence that supports the hypothesis that it is not only pure cholesterol and saturated fats but rather oxidation products of cholesterol and unsaturated fats (and possibly certain pure unsaturated fats) that are atherogenic, possibly by causing endothelial cell injury/dysfiinction. Lipid-mediated endothelial cell dysfunction may lead to adhesion of monocytes, increased permeability of the endothelium to macromolecules, i.e., a decrease in endothelial barrier function, and disturbances in growth control of the vessel wall. 

Lecithin plays an important role in the transport of fats and cholesterol from the liver to sites where they can be either used or stored. Since fats do not dissolve in water solutions like blood plasma, they are transported in spherical particles called lipoproteins. These particles can mix with water solutions because the water-friendly proteins, cholesterol and phospholipids are on the outside surface. The nonpolar fats associated with them make up the core, which is unexposed to water. Because lecithin is required for lipoprotein synthesis, a lecithin deficiency results in fats accumulating in the liver and leads to liver damage. Lecithin deficiency also leads to increased amounts of cholesterol in the blood and atherosclerosis, a disease in which narrowing of the arteries is caused primarily by the deposit of fats from the bloodstream. 

Atherosclerosis and Plasma Lipids - Lipoprotein lipases play a critical role in the metabolism of lipoproteins and thus may be involved in athero-genesis. Hypercholesterolemia in the cholesterol-fed rabbit was attributed to the accumulation of chylomicron remnants, which may be formed on the aorta wall by lipoprotein lipase and deposited in the deep layers of the arterial wall without prior release into the blood stream.13 On this basis, cholesterol-rich lipoproteins in plasma may be the product rather than the cause of the atherogenic process. However, the defect in Type III hyperlipoproteinemia (broad- disease) may be ineffective removal of chylomicron remnant particles from the arterial wall,11 due to a failure of the liver to recognize such particles.15... 

Another factor that regulates HDL cholesterol levels is the plasma level of cholesteryl ester transfer protein (CETP). CETP, a hydrophobic glycoprotein (M.W. 741,000), facilitates the transfer of cholesteryl esters in HDL and triacylglycerols in LDL and VLDL (see above). In CETP deficiency due to a point mutation (G A) in a splice donor site that prevents normal processing of mRNA, the plasma HDL cholesterol levels of affected individuals are markedly high, with decreased LDL cholesterol. In the affected families, there was no evidence of premature atherosclerosis and, in fact, there was a trend toward longevity. These observations support the role of CETP and the antiatherogenic property of HDL. However, not all factors that elevate HDL levels may be... 

Macroangiopathy (or accelerated atherosclerosis) leads to premature coronary heart disea.se. The exact inechanisms for increa.sed susceptibility to atherosclerosis in diabetics are unknown however, hyperlipidaemia and increased protein glycation may play a role. The most common form of hyperlipidaemia observed in diabetics is hypcrtriglyceridaemia with increa.sed plasma VLDL-cholesterol and decreased HDL-choIesterol. 

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