A New Perspective on Cholesterol Metabolism in Man

A NEW PERSPECTIVE ON CHOLESTEROL METABOLISM IN MAN H. S. SODHI* Ever since cholesterol was suspected to play a role in the development of atherosclerotic heart disease, there has been a surge of interest in the study of cholesterol metabolism in man. Although plasma cholesterol constitutes only about 7 percent of the total cholesterol in the body, it is the only pool of cholesterol which has been incriminated in this disease. Plasma cholesterol has therefore been the main focus of attention. Even studies on tissue metabolism of cholesterol are generally viewed in relationship to their bearing directly or indirectly on plasma cholesterol. Although free cholesterol has been recognized to be a structural component of tissue membranes and of plasma lipoproteins, the thinking in this field has been dominated by the "results" rather than the "function" of cholesterol. Traditionally plasma cholesterol is grouped with triglycerides and other plasma lipids, and the teaching has been that the lipids are combined with specific proteins in order to make them water soluble for their transport in plasma. These "apoproteins" serve as solubilizers of plasma lipids, and under most conditions their availability is assumed to be adjusted to the needs for transport of plasma lipids. Although often not stated explicitly, it is generally assumed that there is homeostatic control of plasma cholesterol—that is, that there are mechanisms specifically sensitive to changes in the plasma cholesterol concentration and which come into play in the form of alterations in the absorption of dietary cholesterol or changes in tissue synthesis or catabolism ofendogenous cholesterol. In contrast to the above, I suggest that there are no homeostatic mechanisms specifically sensitive to plasma concentration of cholesterol, and that absorption of dietary cholesterol or the tissue synthesis and catabolism of endogenous cholesterol are not directed specifically to ?Departments of Medicine, University of Saskatchewan, Saskatoon, Canada, and Stanford University, Palo Alto, California. Much of the work was done in collaboration with my colleague Dr. B. J. Kudchodkar and was supported by Medical Research Council of Canada and Canadian and Saskatchewan Heart Foundations. Perspectives in Biology and Medicine · Summer 1975 | 477 maintain levels of plasma cholesterol. Free cholesterol in plasma lipoproteins is viewed as only one of the packaging materials necessary for the transport of the contents of lipoprotein package. Similarly, all free cholesterol in tissues is assumed to be "structural" (except, of course, in organs having special roles in cholesterol metabolism). The tissue metabofam ofcholesterol, in general, relates more to the needs ofthe tüsues than to homeostasis ofplasma cholesterol. The tissue synthesis of free cholesterol is coupled primarily to the need for synthesis and turnover of cellular and subcellular membranes. Synthesis of free cholesterol in organs which make plasma lipoproteins is coupled to the need for synthesis of new plasma lipoproteins as well as to the need for synthesis of cellular organelles . All tissues have some degree ofturnover, but only the liver and intestines synthesize plasma lipoproteins. (Chylomicra for the purposes of this discussion are considered lipoproteins.) That cholesterol synthetic activity in liver and intestines constitutes more than 90 percent of the total synthetic activity in experimental animals [1] suggests that turnover of plasma lipoproteins is associated with much greater synthesis of cholesterol than the turnover of cellular membranes and intracellular organelles. This concept is supported by the demonstration of marked differences in cholesterol synthesis associated with changes limited to hepatic synthesis of plasma lipoproteins in man [2]. Although sufficient information is not yet available, it appears that tissues with faster turnover rates synthesize more cholesterol than those which have relatively slow turnover. The epidermis has a rapid turnover and synthesizes more cholesterol than the dermis, which has a rather slow turnover [3]. The mature nervous tissue and red blood cells have perhaps the least turnover, and they also show little, if any, synthesis of cholesterol [4]. In man the lipoproteins synthesized by the intestines contain both cholesterol esters and triglycerides as their content or "core," but under normal conditions the newly synthesized hepatic lipoproteins are assumed to contain triglycerides as the only or the predominant core lipid [5]. When perfused in vitro, livers from cholesterol-fed rats and containing large amounts of stored cholesterol esters synthesize lipoproteins which transport...