Current Concepts of Cholesterol Metabolism and Their Relationship to Lecithin: Cholesterol Acyltransferase

Abstract

Fig. 1 represents the general consensus on some of the most important aspects of cholesterol metabolism in man. According to the published literature, there is a single pool of free cholesterol in the liver; most of the dietary, biliary, and intestinal cholesterol absorbed from intestines and removed by the liver enters this pool. Cholesterol synthesized by the liver also enters the same pool. Biliary cholesterol and recently synthesized bile acids come from this pool, and the free cholesterol for synthesis of new lipoproteins is also derived from the same pool. In addition. this pool of free cholesterol undergoes isotopic exchange with plasma free cholesterol. The published literaturc does not indicate the presence of any mechanism for transport of net amounts of plasma cholesterol into the liver. This concept (of a single hepatic pool of free cholesterol) suggests that in conditions associated with increased turnover of plasma lipoproteins increased requirements of free cholesterol for synthesis of new lipoproteins can, after a short lag, be met by increased amounts of cholesterol returning to this pool from catabolism of lipoproteins. Over the last few years we investigated the absorption (l), synthesis (2), catabolism (3), and mobilization (4) of tissue cholesterol in hyperlipemic subjects with and without hypertriglyceridemia. There were no differences in the absorption of dietary cholesterol between them, but studies on cholesterol synthesis and turnover indicated that cholesterol synthesis was significantly greater in hypertriglyceridemic subjects than in those who had normal plasma triglycerides. Similarly, fecal metabolites of endogenous cholesterol were also significantly greater in hypertriglyceridemic than in normotriglyceridemic subjects. Since elevation of plasma triglycerides above normal is primarily due to an increase in plasma very low density lipoproteins (VLDL), and since modest to moderate elevations of VLDL are associated with significant increase in their turnover rates (5), it was suggested by us that cholesterol synthesis as well as its catabolism are related to the turnover of plasma lipoproteins (6). The fact that the continued increases in synthesis and catabolism were observed in conditions associated with hypertriglyceridemia suggested to us that at least some of the cholesterol catabolized in the liver was not available for synthesis of new lipoproteins. On the basis of such reasoning, we proposed that the cholesterol synthesized in the liver and the cholesterol in chylomicra and other intestinal lipoproteins removed by the liver enter into a single pool which supplies the free cholesterol for synthesis of new plasma lipoproteins (Fig. 2). On the other hand, cholesterol derived from catabolism of plasma lipoproteins is transported back into a second pool from which biliary cholesterol and bile acids are derived. Although there may be some transfer of cholesterol from one pool to another, functionally the two pools are viewed as