Cholesteryl ,, ^ esters ACAT

Mevalonate x multistep

Cholesterol (intracellular)

- insulin

- glucagon stimulates proteolysis of HMG-CoA reductase

receptor-mediated endocytosis

LDL-cholesterol (extracellular)

FIGURE 21-44 Regulation of cholesterol formation balances synthesis with dietary uptake. Glucagon promotes phosphorylation (inactivation) of HMG-CoA reductase; insulin promotes dephosphoryla-tion (activation). X represents unidentified metabolites of cholesterol that stimulate proteolysis of HMG-CoA reductase.

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 hypercholesterolemia. 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






FIGURE 21-45 Inhibitors of HMG-CoA reductase. A comparison of the structures of mevalonate and four pharmaceutical compounds that inhibit HMG-CoA reductase.

cholesterol-poor HDL is rapidly removed from the blood and destroyed. Both familial HDL deficiency and Tangier disease are very rare (worldwide, fewer than 100 families with Tangier disease are known), but the existence of these diseases establishes a role for ABC1 protein in the regulation of plasma HDL levels. Because low plasma HDL levels correlate with a high incidence of coronary artery disease, the ABC1 protein may prove a useful target for drugs to control HDL levels. ■

Steroid Hormones Are Formed by Side-Chain Cleavage and Oxidation of Cholesterol

Humans derive all their steroid hormones from cholesterol (Fig. 21-46). Two classes of steroid hormones are synthesized in the cortex of the adrenal gland: mineralocorticoids, which control the reabsorption of inorganic ions (Na+, Cl", and HCO3) by the kidney, and glucocorticoids, which help regulate gluconeogene-sis and reduce the inflammatory response. Sex hormones are produced in male and female gonads and the placenta. They include progesterone, which regulates the female reproductive cycle, and androgens (such as testosterone) and estrogens (such as estradiol), which influence the development of


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