C

FIGURE 2-12 Source of the carbon atoms of cholesterol. The different carbon atoms are shown to be derived from either the methyl (M) carbon atom or the carboxyl (C) group of acetate.

terol and bile salts. These relationships are summarized in Figure 2-16.

In an average 70-kg man, «0.8-1.4 g of cholesterol is turned over per day. The daily ingestion of cholesterol in Western countries is 0.5-2.0 g; the efficiency of intestinal absorption ranges from 30 to 50%. However, it is known that dietary cholesterol is not the exclusive source of the bodily pool of cholesterol. The liver and intestine together account for more than 60% of the body's daily synthesis of this sterol. When considering the turnover of body cholesterol, it has been suggested that there are two principal components. Pool A, which comprises 30-35% of the total body cholesterol, consists of the cholesterol in liver, bile, plasma, erythrocytes, and intestine. Pool B constitutes the remaining 65-70% of the exchangeable body cholesterol and principally comprises the cholesterol in the skin, adipose tissue, and skeleton. It is now well established that hepatic cholesterol biosynthesis can be greatly reduced by the ingestion of a cholesterol-rich diet. This prevents excessive cholesterol accumulation through feedback mechanisms operative at the level of the HMG-CoA reductase enzyme. HMG-CoA reductase is the rate-limiting step in the conversion of acetate into cholesterol and thus is a logical site for feedback regulation. Dietary cholesterol does not function as an allosteric modulator directly on the HMG-CoA reductase; instead, it lowers the steady-state level of HMG-CoA reductase by decreasing the rate of biosynthesis of the enzyme without affecting its rate of enzyme degradation. Cholesterol SCP may also affect HMG-CoA reductase by a similar mechanism. The rate of hepatic cholesterol biosynthesis exhibits a marked diurnal variation caused by changes in the level of HMG-CoA reductase.

A wide variety of hormones and some dietary factors have been shown to modulate the biosynthesis of cholesterol (see Table 2-4). Most of these agents are believed to act on HMG-CoA reductase. The steady-state level of HMG-CoA reductase is affected by a complex interplay between insulin, glucagon, triiodothyronine (T3), and growth hormone. A precise understanding of the mechanisms whereby all of these hormones modulate sterol biosynthesis is not

0 0

Post a comment