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...

Abstract-Murine models of atherosclerosis, such as the apolipoprotein E (apoE) or the LDL receptor knockout mice, usually do not exhibit many of the cardinal features of human coronary heart disease (CHD), eg, spontaneous myocardial infarction, severe cardiac dysfunction, and premature death. Here we show that mice with homozygous null mutations in the genes for both the high density lipoprotein receptor SR-BI and apoE (SR-BI/apoE double knockout [dKO] mice) exhibit morphological and functional defects with similarities to those seen in human CHD. When fed a standard chow diet, these hypercholesterolemic animals developed significant atherosclerotic lesions in the aortic sinus as early as 4 to 5 weeks after birth. We now show that they also exhibited extensive lipid-rich coronary artery occlusions and spontaneously developed multiple myocardial infarctions and cardiac dysfunction (eg, enlarged hearts, reduced ejection fraction and contractility, and ECG abnormalities). Their coronary arterial lesions, which were strikingly similar to human atherosclerotic plaques, exhibited evidence of cholesterol clefts and extensive fibrin deposition, indicating hemorrhage and clotting. All of the dKO mice died by 8 weeks of age (50% mortality at 6 weeks). Thus, SR-BI/apoE dKO mice provide a new murine model for CHD and may help better define the role of lipoprotein metabolism and atherosclerosis in the pathogenesis of myocardial infarction and cardiac dysfunction. Furthermore, these animals may be useful for preclinical testing of potential genetic and/or pharmacological therapies for CHD. Key Words: SR-BI/apolipoprotein E knockout mice Ⅲ atherosclerosis Ⅲ myocardial infarction Ⅲ coronary artery disease Ⅲ lipoprotein metabolism O ne of the best understood risk factors for coronary artery atherosclerosis, a leading cause of myocardial infarction (MI) and death, is hypercholesterolemia. Unfortunately, few hypercholesterolemia and atherosclerosis rodent models spontaneously develop MIs and cardiac dysfunction. Fat-fed LDL receptor (LDLR) knockout (KO) 1 and chow-fed apolipoprotein E (apoE) KO mice, 2-4 standard models for hypercholesterolemia/atherosclerosis, do not usually exhibit MI or reduced lifespans; although 24-to 40-week-old, fat-fed apoE KO mice can develop coronary arterial plaques and, occasionally, small areas of myocardial fibrosis. 4,5 ApoE/LDLR double KO mice fed a high-fat/high-cholesterol diet for 7 months have occlusive coronary arterial atherosclerotic lesions and some associated perivascular myocardial scarring. 6 Severe stress exacerbates the small ECG abnormalities seen in these mice at rest and can induce endothelin-dependent MIs, 6 although such MIs were not reported to be lethal. Dahl salt-sensitive, hypertensive rats expressing high levels of human cholesteryl ester transfer protein 7 and atherosclerosisprone male JCR:LA-corpulent rats, 8 which have hyperlipidemia and atherosclerosis, develop coronary artery lesions and MIs.It would be useful to have additional, genetically manipulable, murine models of...