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Unregulated cholesterol production can lead to serious human disease. When the sum of cholesterol synthesized and cholesterol obtained in the diet exceeds the amount required for the synthesis of membranes, bile salts, and steroids, pathological accumulations of cholesterol in blood vessels (atherosclerotic plaques) can develop, resulting in obstruction of blood vessels (atherosclerosis). Heart failure due to occluded coronary arteries is a leading cause of death in industrialized societies. Atherosclerosis is linked to high levels of cholesterol in the blood, and particularly to high levels of LDL-bound cholesterol; there is a negative correlation between HDL levels and arterial disease.

In familial hypercholesterolemia, a human genetic disorder, blood levels of cholesterol are extremely high and severe atherosclerosis develops in childhood. These individuals have a defective LDL receptor and lack receptor-mediated uptake of cholesterol carried by LDL. Consequently, cholesterol is not cleared from the blood; it accumulates and contributes to the formation of atherosclerotic plaques. Endogenous cholesterol synthesis continues despite the excessive cholesterol in the blood, because extracellular cholesterol cannot enter the cell to regulate intracellular synthesis (Fig. 21-44). Two products derived from fungi, lovastatin and com-pactin, are used to treat patients with familial hyper-cholesterolemia. Both these compounds, and several synthetic analogs, resemble mevalonate (Fig. 21-45) and are competitive inhibitors of HMG-CoA reductase, thus inhibiting cholesterol synthesis. Lovastatin treatment lowers serum cholesterol by as much as 30% in individuals having one defective copy of the gene for the LDL receptor. When combined with an edible resin that binds bile acids and prevents their reabsorption from the intestine, the drug is even more effective.

In familial HDL deficiency, HDL levels are very low; they are almost undetectable in Tangier disease. Both genetic disorders are the result of mutations in the ABC1 protein. Cholesterol-depleted HDL cannot take up cholesterol from cells that lack ABC1 protein, and

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