The HDL receptor, scavenger receptor, class B type I (SR-BI), mediates cellular delivery of HDL cholesterol by selective lipid uptake, a mechanism fundamentally different from that of classic receptor-mediated endocytosis (e.g., LDL receptor (LDLR) pathway). SR-BI is a multiligand receptor that can bind LDL and VLDL as well as HDL, and can mediate both cellular uptake of non-lipoprotein cholesterol and cellular cholesterol efflux. It may also be involved in intestinal cholesterol absorption. In vivo studies with mice, including hepatic overexpression of SR-BI and analysis of SR-BI homozygous null mutants (SR-BI KO), have shown that SR-BI plays a key role 1) in determining the levels of plasma HDL and biliary cholesterol and HDL structure, 2) in mediating the regulated delivery of HDL-cholesterol to steroidogenic tissues and the liver, and 3) in protecting against atherosclerosis in some cases. It is also required for normal oocyte development and female fertility. The mechanisms underlying SR-BI's antiatherogenic effects are unknown; however, potential causes of the dramatically accelerated atherosclerosis see in the SR-BI/apoE double Kos relative to the single Kos include: I) changes in relative amounts of cholesterol in proatherogenic and antiatherogenic (e.g., normal HDL lipoproteins, ii) altered flux of cholesterol into or out of the vessel wall, perhaps directly due to abnormal HDL structure or reduced SR-BI-mediated efflux from macrophages, and iii) decreases in overall reverse cholesterol transport, primarily due to loss of SR-BI activity in the liver. The primary goals of this proposal are to test several of these hypotheses and further explore the role of SR-BI in cholesterol metabolism. The work will focus on tissue or cell type-specific expressing or ablation of SR-BI activity in atherosclerosis models (apoE and LDLR KO mice). We will use sense and antisense adenovirus vectors, gene-targeted knockout (KO) mice, and bone marrow transplantation to control the cell and tissue-specific expression or ablation of SR-BI activity, with a special focus on macrophages and the liver. In vitro analyses of atherosclerosis-related functions of normal and SR-BI KO macrophages and or normal and abnormal lipoproteins will be performed. IN addition, we will examine the suggestions that SR-BI may play a role in intestinal cholesterol absorption. The proposed work will help elucidate key molecular and cellular mechanisms underlying lipid lipoprotein and metabolism and atherosclerosis, and may significantly influence the direction of pharmaceutical research and development aimed toward developing new methods for the prevention and treatment of atherosclerosis.
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