Biosynthesis of Cholesterol, Steroids, and Isoprenoids:- Cholesterol Biosynthesis Is Regulated at Several Levels
Cholesterol synthesis is a complex and energy expensive process, so it is clearly advantageous to an organism to regulate the biosynthesis of cholesterol to complement dietary intake. In mammals, cholesterol production is regulated by intracellular cholesterol con centration and by the hormones glucagon and insulin. The rate-limiting step in the pathway to cholesterol (and a major site of regulation) is the conversion of HMG CoA to mevalonate (Fig. 21–34), the reaction catalyzed by HMG-CoA reductase. Regulation in response to cholesterol levels is mediated by an elegant system of transcriptional regulation of the gene encoding HMG-CoA reductase. This gene, along with more than 20 other genes encoding enzymes that mediate the uptake and synthesis of cholesterol and unsaturated fatty acids, is controlled by a small family of proteins called sterol regulatory element-binding proteins (SREBPs). When newly synthesized, these proteins are embedded in the ER. Only the soluble amino terminal domain of an SREBP functions as a transcriptional activator, using mechanisms discussed in Chapter 28. However, this domain has no access to the nucleus and cannot participate in gene activation while it remains part of the SREBP molecule. To activate transcription of the HMG-CoA reductase gene and other genes, the transcriptionally active domain is separated from the rest of the SREBP by proteolytic cleavage. When cholesterol levels are high, SREBPs are inactive, secured to the ER in a complex with another protein called SREBP cleavage-activating protein (SCAP) (Fig. 21–43). It is SCAP that binds cholesterol and a number of other sterols, thus acting as a sterol sensor. When sterol levels are high, the SCAP-SREBP complex prob ably interacts with another protein that retains the en tire complex in the ER. When the level of sterols in the cell declines, a conformational change in SCAP causes release of the SCAP-SREBP complex from the ER retention activity, and the complex migrates within vesicles to the Golgi complex. In the Golgi complex, SREBP is cleaved twice by two different proteases, the second cleavage releasing the amino-terminal domain into the cytosol. This domain travels to the nucleus and activates transcription of its target genes. The amino-terminal domain of SREBP has a short half-life and is rapidly degraded by proteasomes (see Fig. 27–42). When sterol levels increase sufficiently, the proteolytic release of SREBP amino-terminal domains is again blocked, and proteasome degradation of the existing active domains results in a rapid shut-down of the gene targets. Several other mechanisms also regulate cholesterol synthesis (Fig. 21–44). Hormonal control is mediated by covalent modification of HMG-CoA reductase itself. The enzyme exists in phosphorylated (inactive) and dephosphorylated (active) forms. Glucagon stimulates phosphorylation (inactivation), and insulin promotes dephosphorylation, activating the enzyme and favoring cholesterol synthesis. High intracellular concentrations of cholesterol activate ACAT, which increases esterification of cholesterol for storage. Finally, a high cellular cholesterol level diminishes transcription of the gene that encodes the LDL receptor, reducing production of the receptor and thus the uptake of cholesterol from the blood.
FIGURE 21–43 SREBP activation. Sterol regulatory element-binding proteins (SREBPs, shown in green) are embedded in the ER when first synthesized, in a complex with the protein SREBP cleavage-activating protein (SCAP, red). (N and C represent the amino and carboxyl termini of the proteins.) When bound to SCAP, SREBPs are inactive. When sterol levels decline, the complex migrates to the Golgi complex, and SREBP is cleaved by two different proteases in succession. The liberated amino-terminal domain of SREBP migrates to the nucleus, where it activates transcription of sterol-regulated genes.
FIGURE 21–44 Regulation of cholesterol formation balances syn thesis with dietary uptake. Glucagon promotes phosphorylation (in activation) of HMG-CoA reductase; insulin promotes dephosphorylation (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 mem branes, 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 compactin, 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 treat ment 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 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.
FIGURE 21–45 Inhibitors of HMG-CoA reductase. A comparison of the structures of mevalonate and four pharmaceutical compounds that inhibit HMG-CoA reductase.
