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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...

, we showed that SR-BI-mediated cholesterol efflux was highly correlated (r 2 ‫؍‬ 0.985) with HDL phosphatidylcholine content. The effects of varying HDL phospholipid composition on SR-BI-mediated free cholesterol flux were not correlated with changes in either the K d or B max values for high affinity binding to SR-BI. We conclude that SR-BI-mediated free cholesterol flux is highly sensitive to HDL phospholipid composition. Thus, factors that regulate cellular SR-BI expression and the local modification of HDL phospholipid composition will have a large impact on reverse cholesterol transport.The deposition of cholesterol in peripheral cells is opposed by the process of reverse cholesterol transport (RCT) 1 where high density lipoproteins (HDL) remove free cholesterol (FC) from cells and deliver it back to the liver for excretion (1-3). The flux of FC between cells and HDL is bi-directional. Depending on the direction of the FC concentration gradient between cells and lipoproteins, either net efflux or net influx of cholesterol can occur (4, 5). The creation of a cholesterol gradient depends upon many properties of the acceptors and the cell plasma membrane. Such factors include the cholesterol and phospholipid content of the acceptors and plasma membrane (4, 5), the existence of cholesterol domains within the plasma membrane (6 -10), and the size, number, and composition of acceptor particles (11-13).Recent studies have shown that, when cells express scavenger receptor BI (SR-BI), the bi-directional flux of FC between cells and HDL is accelerated (8,14,15). The mechanism by which SR-BI mediates FC flux is uncertain. However, recent studies from our laboratory demonstrated that binding of the acceptor particles to SR-BI is not a requirement for SR-BImediated cholesterol efflux (7,8). Rather SR-BI induces a reorganization of the plasma membrane cholesterol, and this reorganization is linked to enhanced FC flux (7,8,16). Regardless of the mechanism, evidence is accumulating to support the importance of SR-BI-mediated FC flux in RCT. Recent studies of Ji and colleagues (17) showed that either attenuation or overexpression of hepatic SR-BI in mice led to significantly decreased or increased delivery of HDL FC into bile. In addition, the expression of SR-BI in peripheral cells and in foam cells of the arterial wall suggests a role for SR-BI in the removal of FC from the periphery (15, 18, 19).SR-BI-mediated FC flux requires phospholipid in the acceptor (15), and studies have shown that cholesterol efflux from cells is highly correlated with the concentration of HDL phospholipid in serum (20,21). Also, the stimulation of cholesterol efflux upon phospholipid supplementation of serum is closely linked to the levels of SR-BI among cell types (14). These observations are consistent with epidemiological data demonstrating that humans with low HDL phospholipid levels have a high incidence of coronary artery disease (22). These findings suggest that changes in HDL phospholipid content may alter SR-BI-mediated FC flux. The cu...