Scavenger Receptor BI Promotes High Density Lipoprotein-mediated Cellular Cholesterol Efflux

Abstract

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.

Scavenger Receptor Class B Type I Mediates Biliary Cholesterol Secretion Independent of ATP-Binding Cassette Transporter g5/g8 in Mice†

“…SR-BI can mediate bidirectional flux of cholesterol, i.e., influx and efflux depending on a cholesterol gradient. [3][4][5] We speculate that SR-BI at the canalicular membrane might fulfill a similar function, whereby the gradient is provided through constant transport by the biliary secretion process. However, we cannot exclude that SR-BI expression at the canalicular membrane is resulting in more efficient micellization due to an increased cholesterol content of the canalicular membrane.…”

“…1,2 In nonpolarized cells, namely macrophages and the hepatoma cell line Fu5AH, SR-BI expression either results in selective uptake of cholesterol, mainly from high-density lipoprotein (HDL), or in cholesterol efflux toward suitable acceptors. [3][4][5][6] In hepatocytes, which is a highly polarized cell type, SR-BI is the main receptor responsible for selective uptake of cholesterol from plasma HDL. 7 Consequently, hepatic overexpression of SR-BI results in decreased plasma HDL cholesterol levels, [8][9][10] whereas SR-BI knockout mice have increased plasma HDL cholesterol.…”

Discovery of chemical inhibitors of the selective transfer of lipids mediated by the HDL receptor SR-BI

“…Assays for the uptake of lipids from DiI-HDL and [ 3 H]CE-HDL, efflux of [ 3 H]cholesterol from labeled cells, and 125 I-HDL binding were performed as described (1,18,20). In some experiments, values were normalized so that 100% of control represents activity in the absence of compounds and 0% represents activity determined in the presence of a 40-fold excess of unlabeled HDL or, for Y1-BS1 cells, in the presence of a 1:500 dilution of the KKB-1 blocking antibody (generous gift from Karen Kozarsky, Glaxo͞SmithKline Beecham, King of Prussia, PA) (20).…”

“…Although the mechanism of SR-BI-mediated selective lipid uptake and the subsequent intracellular transport of these lipids have only just begun to be explored (2,15,16), they clearly differ fundamentally from the pathway of receptor-mediated endocytosis via clathrin-coated pits and vesicles used by the low-density lipoprotein (LDL) receptor to deliver cholesterol esters from LDL to cells (17). SR-BI also can mediate cholesterol efflux from cells to HDL, although the physiological significance of SR-BI-mediated lipid efflux to lipoproteins is uncertain (18).…”

Participation of macrophages in atherosclerotic lesion morphology in LDLr−/− mice

“…Cholesterol efflux from macrophages can occur by passive aqueous diffusion (29), scavenger receptor class B type I-mediated uptake by HDL (30), and ABCA1-mediated active efflux of phospholipids and cholesterol (31). Cholesterol-enriched vesicles are routed to the plasma membrane and fuse to form cholesterol-rich rafts that donate cholesterol to the membrane.…”