Treatment of lipoprotein disorders is primarily aimed at achieving relatively low VLDL and LDL levels and relatively high HDL levels. Since obesity and insulin resistance are often associated with elevated VLDL, weight loss and exercise are often effective in reducing VLDL. Exercise has an insulin-sensitizing effect on muscle; thus regular exercise can have long-term effects on plasma lipoproteins. Exercise also tends to raise HDL levels. For some people, a reduction in carbohydrate intake (replacing the calories with monounsaturated fat) can lower triglyceride levels, presumably by decreasing the rate of de novo lipogenesis in the liver and adipose tissue.
Drugs derived from fibric acid (p-chlorophenoxyisobutyrate) are widely used to lower triglycerides when diet and exercise fail. These agents increase fatty acid oxidation and decrease VLDL triglyceride secretion. Occasionally, they increase LDL cholesterol and must be used together with an LDL-lowering drug.
Statins are a family of drugs that specifically reduce cholesterol synthesis by inhibiting HMG-CoA reductase. The dearth of cholesterol in the liver leads to upregulation of the LDL receptor (see Fig. 14). In most patients who respond to statins, LDL production is decreased. In addition, there is often an increase in LDL clearance. These drugs are widely used and have made a significant impact on cardiovascular disease in several nations.
Bile acid sequestrants are charged resins that are ingested in a liquid suspension. They bind to bile acids in the intestine and prevent their reabsorption. Since bile acids normally feed back on their own synthesis from cholesterol, these agents evoke a compensatory increase in bile acid synthesis. The diversion of liver cholesterol for bile acid production leads to an upregulation of the LDL receptor and thus a reduction in LDL levels. Because bile acid sequestrants increase cholesterol catabolism and statins decrease cholesterol synthesis, the two agents together act synergistically.
The majority of people with low HDL have high triglycerides. Their HDL levels usually rise if their triglyceride levels are reduced. However, a significant number of people have low HDL and normal triglycerides; they have primary hypoalphalipoproteinemia. The treatment options for these individuals are limited. Thus, the next frontier in drug development is to develop treatments for low HDL or ones that enhance the catabolism of cholesterol. The discovery of lipid transport proteins such as ABCA1 provides potential new targets for drug development.
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