No abstract

Abstract-The removal of excess free cholesterol from cells by HDL or its apolipoproteins is important for maintaining cellular cholesterol homeostasis. This process is most likely compromised in the atherosclerotic lesion because the development of atherosclerosis is associated with low HDL cholesterol. Multiple mechanisms for efflux of cell cholesterol exist. Efflux of free cholesterol via aqueous diffusion occurs with all cell types but is inefficient. Efflux of cholesterol is accelerated when scavenger receptor class-B type I (SR-BI) is present in the cell plasma membrane. Both diffusion-mediated and SR-BI-mediated efflux occur to phospholipid-containing acceptors (ie, HDL and lipidated apolipoproteins); in both cases, the flux of cholesterol is bidirectional, with the direction of net flux depending on the cholesterol gradient. The ATP-binding cassette transporter AI (ABCA1) mediates efflux of both cellular cholesterol and phospholipid. In contrast to SR-BI-mediated flux, efflux via ABCA1 is unidirectional, occurring to lipid-poor apolipoproteins. The relative importance of the SR-BI and ABCA1 efflux pathways in preventing the development of atherosclerotic plaque is not known but will depend on the expression levels of the two proteins and on the type of cholesterol acceptors available. Key Words: cholesterol efflux Ⅲ scavenger receptor class-BI Ⅲ ATP-binding cassette transporter AI Ⅲ reverse cholesterol transport H DL levels are inversely correlated with the incidence of coronary artery disease. 1-4 A long-standing hypothesis to explain this protective effect of HDL against atherosclerosis is the process of reverse cholesterol transport (RCT). 5 In RCT, HDL or its apolipoproteins mediate the removal of excess free cholesterol (FC) from peripheral cells and, after a series of reactions in plasma, the cholesterol is delivered via either LDL or HDL to the liver for excretion into the bile. The flux of FC between cells and extracellular acceptors is important at two points in the RCT pathway: (1) the removal of FC from peripheral cells and (2) the delivery of HDL FC to the liver. There are 3 known mechanisms of FC flux: (1) aqueous diffusion, (2) SR-BI-mediated FC flux, and (3) ABCA1-mediated efflux (Figure 1). The purpose of this review is to discuss each mechanism and the relative importance of each mechanism to RCT. Aqueous DiffusionCholesterol molecules are sufficiently water-soluble to be able to transfer from either model 6 or cell membranes 7 to an acceptor by the so-called aqueous diffusion mechanism. 8 This process involves desorption of cholesterol molecules from the donor lipid-water interface and diffusion of these molecules through the intervening aqueous phase until they collide with and are absorbed by an acceptor. At a constant donor particle concentration, there is a hyperbolic dependence of cholesterol transfer rate on the concentration of acceptor particles; the kinetics can be described in terms of the rate constants for At lower acceptor concentrations, the transfer rate is dependent on th...