Plasma cholesterol, regulation

LDL and HDL The level of plasma cholesterol is not precisely regulated, but rather varies in response to the diet. Elevated levels result in an increased risk for cardiovascular disease (Figue 27.9). The risk increases progressively with higher values fa-serum total cholesterol. A much stronger correlation exists between the levels of blood LDL cholesterol and heart disease. In contrast, high levels of HDL cholesterol have been associated... 

Kesaniemi, Y.A. and Miettinen, T.A. 1987. Cholesterol absorption efficiency regulates plasma cholesterol level in the Finnish population. Ear. J. Clin. Invest. 17, 391-395. 

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). 

Clinical studies show that dietary cholesterol is a less potent regulator of plasma cholesterol than are saturated fatty acids. Results from meta-analyses predict that plasma cholesterol response to a 100 mg/day change in dietary cholesterol will be from 0.06 to 0.07 mmol/L. The data show that although dietary cholesterol elevates plasma total cholesterol and LDL-cholesterol level, it also increases the level of HDL-cholesterol such that there is little overall effect on the LDL HDL ratio (McNamara, 2000). 

Apo A-II accounts for about 20% of the protein in HDL. Apo A-II s function is not clear. When rare genetic mutations in the gene coding for apo A-Il do occur, they seem not to lead to atherosclerosis. In fact, humans and mice lacking apo A-Il have reduced levels of plasma cholesterol (Weng and Breslow, 1996). Apo A-II seems to function to regulate Che size of the HDL particles. 

Patients with familial hypercholesterolaemia exhibit lower levels of plasma cholesterol after an operation for portacaval anastomosis, and it has now been shown in rats that such an operation causes an increase in HMG-CoA reductase and cholesterol 7a -hydroxylase activities. Many transplantable human and rodent hepatomas do not control the rate of sterol biosynthesis and HMG-CoA reductase levels in response to dietary cholesterol as normal liver cells do. However, certain hepatoma cells have now been found that, although lacking feedback regulation of choles-terologenesis in vivo, retain their regulatory ability in vitro It thus appears that malignant transformation is not necessarily linked to the loss of regulation by the cell of HMG-CoA reductase activity or sterol synthesis. 

LDL-receptor deficiency. In the normal condition (a), VLDL produced by the liver loses triacylglycerol as free fatty acids (FFA) via lipoprotein lipase to peripheral tissues and then proceeds down the metabolic cascade to IDL and LDL. A major portion of these two lipoprotein species is taken up by the liver or peripheral tissues via the LDL (apo B, E) receptor. In individuals with down-regulated or genetically defective LDL receptors (b), the residence time in the plasma of IDL is increa.sed, a greater proportion being converted to LDL. LDL production and turnover time are increased, and total plasma cholesterol levels become grossly abnormal. 

As noted above, there is substantial evidence that the rate of cholesterol synthesis in the small intestinal mucosa can be regulated by changing the circulating levels of plasma cholesterol. Nevertheless, there is relatively little information on the importance of the intestine as a site for the uptake and degradation of lipoproteins and, particularly, of LDL. 

Because the risk for atherosclerotic disease is directly proportional to the plasma levels of LDL cholesterol and inversely proportional to those of HDL cholesterol, a major public health goal has been to lower LDL and raise HDL cholesterol levels. The most successful drug Interventions to date have been aimed at reducing plasma LDL. The steady-state levels of plasma LDL are determined by the relative rates of LDL formation and LDL removal or clearance. LDL receptors, especially those expressed In the liver, play a major role in clearing LDL from the plasma. The liver Is key In cholesterol regulation not only because It Is the site of about 70 percent of the body s LDL receptors, but also because it is the site where unesterified cholesterol and Its bile acid... 

Introduction of the statins in the mid-1980s transformed cholesterol management [38]. Isolated from the culture broths of penicilhns in the 1970s, they proved to be specific, competitive inhibitors of HMG CoA reductase (3-hydoxy 3-methylglutaryl coenzyme A reductase). This enzyme converts HMG CoA into mevalonate, the first committed step in cholesterol synthesis and an important site of metabolic control. The reduction in hepatic cholesterol synthesis (approximately 40% in vivo) results in up-regulation of LDL receptor activity with binding and uptake of plasma LDL to restore hepatic cholesterol balance. The activity of the LDL receptor is a major determinant of plasma cholesterol levels. These mechanisms are now well understood at a molecular level. 

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