Plasma high density lipoprotein (HDL), which protects against atherosclerosis, is thought to remove cholesterol from peripheral tissues and to deliver cholesteryl esters via a selective uptake pathway to the liver (reverse cholesterol transport) and steroidogenic tissues (e.g., adrenal gland for storage and hormone synthesis). Despite its physiologic and pathophysiologic importance, the cellular metabolism of HDL has not been well defined. The class B, type I scavenger receptor (SR-BI) has been proposed to play an important role in HDL metabolism because (i) it is a cell surface HDL receptor which mediates selective cholesterol uptake in cultured cells, (ii) its physiologically regulated expression is most abundant in the liver and steroidogenic tissues, and (iii) hepatic overexpression dramatically lowers plasma HDL. To test directly the normal role of SR-BI in HDL metabolism, we generated mice with a targeted null mutation in the SR-BI gene. In heterozygous and homozygous mutants relative to wild-type controls, plasma cholesterol concentrations were increased by Ϸ31% and 125%, respectively, because of the formation of large, apolipoprotein A-I (apoA-I)-containing particles, and adrenal gland cholesterol content decreased by 42% and 72%, respectively. The plasma concentration of apoA-I, the major protein in HDL, was unchanged in the mutants. This, in conjunction with the increased lipoprotein size, suggests that the increased plasma cholesterol in the mutants was due to decreased selective cholesterol uptake. These results provide strong support for the proposal that in mice the gene encoding SR-BI plays a key role in determining the levels of plasma lipoprotein cholesterol (primarily HDL) and the accumulation of cholesterol stores in the adrenal gland. If it has a similar role in controlling plasma HDL in humans, SR-BI may inf luence the development and progression of atherosclerosis and may be an attractive candidate for therapeutic intervention in this disease.

The high density lipoprotein (HDL) receptor SR-BI (scavenger receptor class B type I) mediates the selective uptake of plasma HDL cholesterol by the liver and steroidogenic tissues. As a consequence, SR-BI can inf luence plasma HDL cholesterol levels, HDL structure, biliary cholesterol concentrations, and the uptake, storage, and utilization of cholesterol by steroid hormone-producing cells. Here we used homozygous null SR-BI knockout mice to show that SR-BI is required for maintaining normal biliary cholesterol levels, oocyte development, and female fertility. We also used SR-BI͞apolipoprotein E double homozygous knockout mice to show that SR-BI can protect against early-onset atherosclerosis. Although the mechanisms underlying the effects of SR-BI loss on reproduction and atherosclerosis have not been established, potential causes include changes in (i) plasma lipoprotein levels and͞or structure, (ii) cholesterol f lux into or out of peripheral tissues (ovary, aortic wall), and (iii) reverse cholesterol transport, as indicated by the significant reduction of gallbladder bile cholesterol levels in SR-BI and SR-BI͞apolipoprotein E double knockout mice relative to controls. If SR-BI has similar activities in humans, it may become an attractive target for therapeutic intervention in a variety of diseases.High density lipoprotein (HDL)-cholesterol levels are inversely proportional to the risk for atherosclerosis (1). This may be due partly to ''reverse cholesterol transport'' (RCT), in which HDL is proposed to remove excess cholesterol from cells, including those in the artery wall (2-7), and transport it, either indirectly or directly (8, 9), to the liver for biliary secretion. HDL also can deliver cholesterol directly to steroidogenic tissues (adrenal gland, testis, ovary) for storage in cytoplasmic cholesteryl ester droplets and for steroid hormone synthesis (10-12). Thus, HDL may influence a variety of endocrine functions, including reproduction. A key mechanism of receptor-mediated direct delivery of HDL cholesteryl esters to the liver and steroidogenic tissues is selective cholesterol uptake, in which only the cholesteryl esters of the HDL particles (not the apolipoproteins) are transferred efficiently to cells (8, 9).The class B type I scavenger receptor, SR-BI, is a cellsurface HDL receptor that mediates selective lipid uptake (13-21; reviewed in refs. 22 and 23). It is most highly expressed in the liver and steroidogenic tissues, in which its activity is regulated by trophic hormones (13, 24-31). As a consequence, SR-BI is a key regulator of HDL cholesterol levels (17-21) and adrenal cholesterol stores (18). The finding that hepatic SR-BI overexpression leads to significant increases in biliary cholesterol content (17, 32) is consistent with gene-targeting studies (18,19) that suggest an important role for SR-BI in RCT. In addition to HDL, SR-BI can bind other ligands, including lipoproteins [LDL, modified LDL, very low density lipoprotein (VLDL)] and apolipoproteins (33-37), and can mediate efflux...

Lipid A is the active moiety of lipopolysaccharide (LPS, also referred to as endotoxin), a surface component of Gram-negative bacteria that stimulates macrophage activation and causes endotoxic shock. Macrophages can bind, internalize and partially degrade LPS, lipid A and its bioactive precursor, lipid IVA. We report here that lipid IVA binding and subsequent metabolism to a less active form by macrophage-like RAW 264.7 cells is mediated by the macrophage scavenger receptor. Scavenger-receptor ligands inhibit lipid IVA binding to, and metabolism by, RAW cells, and lipid IVA binds to type I and type II bovine scavenger receptors on transfected Chinese hamster ovary cells. Although in vitro competition studies with RAW cells indicate that scavenger receptor binding is not involved in LPS or lipid IVA-induced stimulation of macrophages, in vivo studies show that scavenger-receptor ligands greatly inhibit hepatic uptake of lipid IVA in mice. Thus, scavenger receptors expressed on macrophages may have an important role in the clearance and detoxification of endotoxin in animals.