International Congress of Biochemistry and Molecular Biology Satellite Conference: Cellular Cholesterol Ester Metabolism

Abstract

A 1-day satellite conference to the International Congress of Biochemistry and Molecular Biology entitled “Cellular Cholesterol Ester Metabolism” was held at the University of California, San Francisco on August 23, 1997. It was organized to bring together individuals from different disciplines to exchange ideas and information in this important area. Cellular cholesteryl ester metabolism plays a key role in maintenance of cholesterol homeostasis which is vital for normal cell growth and function. The Conference began with an overview by John Dietschy (UT, Southwestern) on the physiological importance of the cholesterol esterification/hydrolysis system. Although acyl coenzyme A:cholesterol acyltransferase (ACAT) often is said to protect cells from a sudden influx of large amounts of cholesterol, this is an uncommon event physiologically. More commonly, ACAT (along with cholesteryl ester hydrolases, CEH) is responsible for maintaining cellular steady-state levels of cholesteryl esters. In vivo, as in vitro, the level of esterification appears to be driven in part by availability of cholesterol and fatty acids. Feeding cholesterol to a new steady state expands both the unesterified and esterified levels of cholesterol, while feeding different fatty acids significantly shifts the ratio between these two components. In humans, as well as in experimental animals, the levels of both dietary cholesterol and fatty acids profoundly affect the steadystate levels of cholesteryl esters in the liver, the level of hepatic low density lipoprotein (LDL) receptor activity and the outflow of cholesterol in VLDL particles. Further, one of the causes of variable responses of the LDL level to cholesterol challenge is mediated by differences in the amount of cholesterol absorbed across the gastrointestinal tract which in turn appears to be dependent on intestinal ACAT levels. Clearly, it is essential that future work include identification of the genes involved and that appropriate studies be undertaken to identify how these enzymes are regulated and whether they are responsible for genetic differences in responses of the plasma LDL level to dietary challenge. The first session, “Physiology/Pathophysiology of Cholesterol Esters,” chaired by Richard Havel (UCSF) and Jane Glick (University of Pennsylvania), opened with a discussion by Larry Rudel (Bowman Gray) of relationships between hepatic production and secretion of cholesteryl esters and atherosclerosis in African green monkeys. Although plasma apoB and LDL cholesterol concentrations were lower in monkeys fed monounsaturated and polyunsaturated fat than in those fed saturated fat, LDL particles in the monounsaturated fat group were remarkably enriched in cholesteryl oleate and the livers of this group had significantly higher cholesteryl ester concentrations. Liver cholesteryl ester content, plasma cholesterol and apoB levels, liver perfusate cholesteryl ester accumulation rate, hepatic ACAT activity, and coronary artery cholesteryl ester concentration were all highly correlated in each group. These data provide the first direct demonstration of the importance of hepatic cholesteryl ester synthesis and secretion in the development of atherosclerosis in primates.