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.

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Scavenger receptor BI (SR-BI) is known to mediate the selective uptake of high density lipoprotein (HDL) cholesteryl ester (CE) in liver and steroidogenic tissues. To evaluate the role of SR-BI in plasma lipoprotein metabolism, we have generated transgenic mice with liverspecific overexpression of murine SR-BI. On a chow diet SR-BI transgenic (SR-BI Tg) mice have decreased HDL-CE, apoA-I, and apoA-II levels; plasma triglycerides, low density lipoprotein (LDL) cholesterol, and very low density lipoprotein (VLDL) and LDL apoB were also decreased, compared with control mice. Turnover studies using non-degradable CE and protein labels showed markedly increased total and selective uptake of HDL-CE in the liver and increased HDL protein catabolism in both liver and kidney. To evaluate the changes in apoB further, mice were challenged with high fat, high cholesterol diets. In SR-BI Tg mice plasma apoB levels were only 3-15% of control levels, and the dietary increase in VLDL and LDL apoB was virtually abolished. These studies show that steady state overexpression of hepatic SR-BI reduces HDL levels and increases reverse cholesterol transport. They also indicate that SR-BI can play a role in the metabolism of apoB-containing lipoproteins. The dual effects of increased reverse cholesterol transport and lowering of apoB-containing lipoproteins that result from hepatic SR-BI overexpression could have anti-atherogenic consequences.The risk of coronary heart disease is inversely correlated with the levels of plasma high density lipoproteins (HDL) 1 (1, 2). HDL appears to transport cholesterol from peripheral tissues to the liver for catabolism and secretion (reverse cholesterol transport) (3, 4). A putative cell-surface receptor for this process has been identified (5). This receptor, scavenger receptor BI (SR-BI), mediates high affinity binding of HDL and the selective uptake of HDL cholesteryl ester (CE) (5), a process for delivery of cholesteryl ester into cells without degradation of HDL proteins (6). Furthermore, SR-BI mRNA and protein levels are highest in adrenal gland, ovary, testis, and liver, tissues that display greatest selective cholesteryl ester uptake from HDL (7-9). SR-BI expression in steroidogenic cells is regulated by hormones and mutations that alter cholesterol supply or metabolism in those tissues in vivo (8 -11). More recently, strong support for the role of SR-BI in HDL metabolism has been provided by studies of mice with a targeted mutation resulting in decreased SR-BI gene expression (12, 13). These mice demonstrate increased plasma HDL cholesterol, decreased adrenal cholesterol content (12, 13), and decreased hepatic fractional clearance rate (FCR) for HDL-CE (13), suggesting that SR-BI is the major molecule mediating HDL-CEselective uptake in the liver. By contrast, adenovirus-mediated, hepatic overexpression of SR-BI in mice results in depletion of plasma HDL and an increase in biliary cholesterol concentration (14). Although these studies nicely demonstrate the effect of acute overexpression of ...

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.

The clearance of free cholesterol from plasma lipoproteins by tissues is of major quantitative importance, but it is not known whether this is passive or receptormediated. Based Plasma high density lipoprotein (HDL)1 plays a key role in maintaining cholesterol homeostasis. Epidemiological studies demonstrated a strong inverse correlation between HDL levels and the risk of coronary artery disease (1). Although detailed mechanisms remain uncertain, it has been proposed that HDL promotes reverse cholesterol transport by facilitating transfer of cholesterol from peripheral tissues to the liver for secretion into bile (Ref. 2; see Ref. 3 for a recent review). Early studies using HDL and low density lipoprotein (LDL) with radiolabeled free cholesterol (FC) showed that FC in HDL is the preferred source for biliary cholesterol (4 -8). Recent work with plant sterols provided further evidence that HDL is the preferred carrier for the transport of cholesterol into bile (9). Based on the observations that HDL FC is preferentially utilized for biliary secretion and that, in tissue culture studies, HDL, but not LDL, selectively binds FC (10), Schwartz et al. (5) predicted that a cell-surface HDL receptor might be involved in the hepatic uptake of HDL FC. As a counterpoint to this idea, free cholesterol exchanges readily between lipoproteins and cells, suggesting that passive FC uptake by the liver might be possible.Scavenger receptor BI (SR-BI) has recently been identified as an authentic HDL receptor that mediates the selective uptake of HDL cholesteryl ester (CE) (11) and bi-directional transfer of FC between HDL and cells (12, 13). Its tissue distribution (11,14) and regulatable expression in the adrenal gland, testis, and ovary (14, 15) indicate that the receptor plays an important physiological role in cholesterol metabolism (16,17). Hepatic overexpression of SR-BI leads to decreased HDL levels in mice (18 -20) due to accelerated hepatic uptake of HDL CE and subsequently increased HDL CE and protein catabolism (19). On the other hand, decreased expression of SR-BI in gene-targeted mice results in increased HDL levels (21, 22). Furthermore, SR-BI mRNA is expressed in thickened intima of atheromatous aorta (12), and the receptor suppresses the development of atherosclerosis in SR-BI transgenic (SR-BI Tg)/LDL receptor-deficient compound mice fed the Paigen diet (23).In our previous work, we found that, in transfected Chinese hamster ovary cells, SR-BI mediates the cellular uptake of HDL FC as well as CE (12). Moreover, SR-BI promotes cholesterol efflux from cells to HDL (12, 13) or protein-free phospholipid (PL) vesicles (13), and the efflux rates correlate with the expression level of SR-BI in different cell lines (Refs. 12 and 13; see Ref. 24 for review). In mice with hepatic overexpression of SR-BI, the biliary concentration of cholesterol is increased (18,25). These results led us to hypothesize that SR-BI plays a physiological role in vivo in promoting the hepatic uptake of HDL FC and facilitating the secretion of...