Scavenger receptor BI (SR-BIThe levels of plasma high density lipoproteins (HDL) 1 are inversely related to the incidence of atherosclerosis and coronary artery disease (1, 2). The protective effect of HDL is thought to involve the reverse transport of cholesterol from cells in the arterial wall to the liver for disposal (3, 4). The transfer of cholesterol from cells to HDL may result from aqueous diffusion (5, 6) and/or the interaction between a cell surface receptor and HDL (7). A number of HDL-binding proteins have been described (5, 7) but none has been shown to be an authentic HDL receptor mediating cholesterol efflux. Recently a member of the scavenger receptor family, scavenger receptor type B class I (SR-BI), was shown to bind HDL with high affinity and to mediate the selective cellular uptake of HDL cholesteryl ester (CE) (8). SR-BI is highly expressed in steroidogenic tissues and the liver (8 -11), and in vivo evidence suggests that SR-BI expression is under feedback regulation (10). While these results show that SR-BI is an HDL receptor that is likely to provide sterol for steroidogenesis, the exact role of SR-BI in the regulation of HDL metabolism and the maintenance of general cholesterol homeostasis is unknown.In the present study we used SR-BI-transfected cells to evaluate a possible role of SR-BI in HDL-mediated cellular cholesterol efflux. We also sought to establish a relationship between cholesterol efflux and the level of SR-BI expression in a variety of cell types. The results, together with our finding that SR-BI mRNA is expressed in the thickened intima of atheromatous aorta, suggest a potentially important role of SR-BI in the initial steps of cholesterol efflux in the arterial wall.

We recently reported that the rate of efflux of cholesterol from cells to high density lipoprotein (HDL) was related to the expression level of scavenger receptor class B type I (SR-BI). Moreover, the expression of this receptor in atheromatous arteries raises the possibility that SR-BI mediates cholesterol efflux in the arterial wall (Ji, Y., Jian, B., Wang, N., Sun, Y., de la Llera Moya, M., Phillips, M. C., Rothblat, G. H., Swaney, J. B., and Tall, A. R. (1997) J. Biol. Chem. 272, 20982-20985). In this paper we describe studies that suggest that the presence of phospholipid on acceptor particles plays an important role in modulating interaction with the SR-BI. Specifically, enrichment of serum with phospholipid resulted in marked stimulation of cholesterol efflux from cells that had higher levels of SR-BI expression, like Fu5AH or Y1-BS1 cells, and little or no stimulation in cells with low SR-BI levels, such as Y-1 cells. Stimulation of efflux by phospholipid enrichment was also a function of SR-BI levels in Chinese hamster ovary cells transfected with the SR-BI gene. Efflux to protein-free vesicles prepared with 1-palmitoyl-2-oleoylphosphatidyl-choline also correlated with SR-BI levels, suggesting that phospholipid, as well as protein, influences the interaction that results in cholesterol efflux. By contrast, cholesterol efflux from a non-cell donor showed no stimulation consequent to phospholipid enrichment of the serum acceptor. These results may help to explain observations in the literature that document an increased risk of atherosclerosis in patients with depressed levels of HDL phospholipid even in the face of normal HDL cholesterol levels.

Purified fractions of three major rat high-density lipoproteins (HDL) and one rat very low-density lipoprotein (VLDL) were isolated by Sephadex gel chromatography or preparative sodium dodecyl sulfate gel electrophoresis. These proteins were characterized by amino acid analysis, end-group analysis, molecular-weight determination, polyacrylamide gel electrophoresis, and circular dichroism. One of these rat proteins, of molecular weight 27 000, appears to be homologous with the human A-I protein. However, rat HDL possesses two additional major components not reported in human HDL - an arginine-rich protein of molecular weight 35 000 and a protein of molecular weight 46 000. The arginine-rich protein of the rat is similar in size and amino acid analysis to the arginine-rich protein reported in human VLDL. A major component of rat VLDL of 35 000 molecular weight appears similar or identical to the arginine-rich protein in rat HDL by every criterion employed for their characterization.

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