Mechanisms and consequences of cellular cholesterol exchange and transfer

Abstract

It is apparent from consideration of the reactions involved in cellular cholesterol homeostasis that passive transfer of unesterified cholesterol molecules plays a role in cholesterol transport in vivo. Studies in model systems have established that free cholesterol molecules can transfer between membranes by diffusion through the intervening aqueous layer. Desorption of free cholesterol molecules from the donor lipid-water interface is rate-limiting for the overall transfer process and the rate of this step is influenced by interactions of free cholesterol molecules with neighboring phospholipid molecules. The influence of phospholipid unsaturation and sphingomyelin content on the rate of free cholesterol exchange are known in pure phospholipid bilayers and similar effects probably occur in cell membranes. The rate of free cholesterol clearance from cells is determined by the structure of the plasma membrane. It follows that the physical state of free cholesterol in the plasma membrane is important for the kinetics of cholesterol clearance and cell cholesterol homeostasis, as well as the structure of the plasma membrane. Bidirectional flux of free cholesterol between cells and lipoproteins occurs and rate constants characteristic of influx and efflux can be measured. The direction of any net transfer of free cholesterol is determined by the relative free cholesterol/phospholipid molar ratios of the donor and acceptor particles. Cholesterol diffuses down its gradient of chemical potential generally partitioning to the phospholipid-rich particle. Such a surface transfer process can lead to delivery of cholesterol to cells. This mechanism operates independently of any lipoprotein internalization by receptor-mediated endocytosis. The influence of enzymes such as lecithin-cholesterol acyltransferase and hepatic lipase on the direction of net transfer of free cholesterol between lipoproteins and cells can be understood in terms of their effects on the pool sizes and the rate constants for influx and efflux. Excess accumulation of free cholesterol in cells stimulates the rate of cholesteryl ester formation and induces deposition of cholesteryl ester inclusions in the cytoplasm similar to the situation in the 'foam' cells of atherosclerotic plaque. Clearance of cellular cholesteryl ester requires initial hydrolysis to free cholesterol followed by efflux of this free cholesterol. The rate of clearance of cholesteryl ester from cytoplasmic droplets is influenced by the physical state of the cholesteryl ester; liquid-crystalline cholesteryl ester is removed more slowly than cholesteryl ester in a liquid state.(ABSTRACT TRUNCATED AT 400 WORDS)