Scavenger receptor BI (SR-BI) is a cell surface receptor that binds high density lipoproteins (HDL) and mediates selective uptake of HDL cholesteryl esters (CE) in transfected cells. To address the physiological role of SR-BI in HDL cholesterol homeostasis, mice were generated bearing an SR-BI promoter mutation that resulted in decreased expression of the receptor in homozygous mutant (designated SR-BI att) mice. Hepatic expression of the receptor was reduced by 53% with a corresponding increase in total plasma cholesterol levels of 50-70% in SR-BI att mice, attributable almost exclusively to elevated plasma HDL. In addition to increased HDL-CE, HDL phospholipids and apo A-1 levels were elevated, and there was an increase in HDL particle size in mutant mice. Metabolic studies using HDL bearing nondegradable radiolabels in both the protein and lipid components demonstrated that reducing hepatic SR-BI expression by half was associated with a decrease of 47% in selective uptake of CE by the liver, and a corresponding reduction of 53% in selective removal of HDL-CE from plasma. Taken together, these findings strongly support a pivotal role for hepatic SR-BI expression in regulating plasma HDL levels and indicate that SR-BI is the major molecule mediating selective CE uptake by the liver. The inverse correlation between plasma HDL levels and atherosclerosis further suggests that SR-BI may inf luence the development of coronary artery disease.It is well established that plasma concentrations of high density lipoprotein (HDL) cholesterol are inversely proportional to the risk of developing atherosclerosis and coronary artery disease (1). Although the protective mechanism is not known, HDL is thought to reduce plaque formation by removing cholesterol from arterial cells and delivering it to the liver as cholesteryl ester (CE) for bile acid synthesis and secretion, a process referred to as reverse cholesterol transport (2). HDL also delivers CE to steroidogenic tissues (adrenal gland, ovary, and testis), where it serves as substrate for steroid hormone synthesis (reviewed in ref.3). The uptake of HDL cholesterol by cells involves selective transfer of CE to the cell without uptake and degradation of HDL proteins, a process known as selective lipid uptake (4, 5). This is markedly different from the mechanism of clearance of low density lipoproteins (LDL), which involves receptor-mediated endocytosis and intracellular degradation of the entire lipoprotein particle (6).Whereas the receptor that mediates LDL clearance was identified well over a decade ago (6), a functional HDL receptor has only recently been identified. Acton et al. (7) demonstrated that scavenger receptor BI (SR-BI), a multiligand cell surface receptor isolated from Chinese hamster ovary cells by expression cloning (8), binds HDL with high affinity and mediates selective cholesterol uptake in transfected cells. Furthermore, the receptor is primarily expressed in those tissues exhibiting selective lipid uptake in vivo: liver, adrenal gland, ovary, ...

Abstract-Scavenger receptor BI (SR-BI) is a multiligand cell-surface receptor that plays a central role in high density lipoprotein homeostasis in rodents. To investigate a role for SR-BI in atherosclerosis, mice with attenuated SR-BI expression were crossed with low density lipoprotein (LDL) receptor-deficient mice. Compound-homozygous mutants showed increased plasma cholesterol, surprisingly due primarily to increased LDL cholesterol and apolipoprotein B levels. LDL turnover studies showed that this resulted from increased LDL cholesterol production rather than decreased LDL catabolism. Atherosclerotic lesion size was significantly increased in male compound-mutant mice relative to LDL receptor-deficient controls (93 427Ϯ16 079 versus 34 448Ϯ5 331 m 2 , respectively; Pϭ0.003). The proatherogenic effect of attenuated SR-BI expression may in part be due to increased LDL cholesterol levels. These findings suggest that upregulation of the receptor could have therapeutic potential for the treatment of atherosclerosis. Key Words: scavenger receptor BI Ⅲ atherosclerosis Ⅲ HDL Ⅲ cholesterol Ⅲ mouse T he risk of developing atherosclerosis and coronary heart disease is inversely proportional to the plasma concentrations of HDL cholesterol and directly related to the levels of LDL cholesterol. 1 The regulation of plasma LDL cholesterol levels via receptor-mediated clearance is a well-defined process involving endocytosis and degradation of the entire LDL particle. 2 In contrast, it has long been known that clearance of plasma HDL cholesterol occurs in part by the fundamentally different process of selective lipid uptake, in which cholesteryl ester (CE) is selectively extracted from HDL particles without concomitant degradation of apoproteins. 3,4 It is only recently that the receptor mediating this process, scavenger receptor BI (SR-BI), has been identified. SR-BI is a cell-surface glycoprotein that has been shown to bind HDL with high affinity and to mediate selective lipid uptake in transfected cells. 5 As expected for an HDL receptor, SR-BI is primarily expressed in those tissues (liver, adrenal gland, ovary, testis) that are the principal sites of selective uptake in vivo. [5][6][7] Definitive evidence for a physiological role of SR-BI in mediating HDL cholesterol clearance in vivo has been recently provided by mouse models. Hepatic overexpression of SR-BI results in depletion of plasma HDL cholesterol, increased hepatic selective uptake of HDL cholesterol, and elevated biliary cholesterol. 8,9 In contrast, reduction of SR-BI expression via gene targeting results in mice with elevated plasma HDL cholesterol levels and decreased hepatic selective uptake of HDL cholesterol. 10,11 The importance of SR-BI in HDL homeostasis suggests a role for the receptor in determining susceptibility to atherosclerosis. An antiatherogenic effect of hepatic SR-BI overexpression has been reported in LDL receptor (LDLr) -deficient mice, 12 but these observations are based on SR-BI expression levels that are nonphysiological. To evaluate t...

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