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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL064737-04
Application #
6638625
Study Section
Pathology A Study Section (PTHA)
Program Officer
Applebaum-Bowden, Deborah
Project Start
2000-04-01
Project End
2005-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
4
Fiscal Year
2003
Total Cost
$468,138
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02139
Fenske, Sara A; Yesilaltay, Ayce; Pal, Rinku et al. (2009) Normal hepatic cell surface localization of the high density lipoprotein receptor, scavenger receptor class B, type I, depends on all four PDZ domains of PDZK1. J Biol Chem 284:5797-806
Kocher, Olivier; Krieger, Monty (2009) Role of the adaptor protein PDZK1 in controlling the HDL receptor SR-BI. Curr Opin Lipidol 20:236-41
Fenske, Sara A; Yesilaltay, Ayce; Pal, Rinku et al. (2008) Overexpression of the PDZ1 domain of PDZK1 blocks the activity of hepatic scavenger receptor, class B, type I by altering its abundance and cellular localization. J Biol Chem 283:22097-104
Kocher, Olivier; Yesilaltay, Ayce; Shen, Ching-Hung et al. (2008) Influence of PDZK1 on lipoprotein metabolism and atherosclerosis. Biochim Biophys Acta 1782:310-6
Yesilaltay, Ayce; Morales, Maria Gabriela; Amigo, Ludwig et al. (2006) Effects of hepatic expression of the high-density lipoprotein receptor SR-BI on lipoprotein metabolism and female fertility. Endocrinology 147:1577-88
Yesilaltay, Ayce; Kocher, Olivier; Pal, Rinku et al. (2006) PDZK1 is required for maintaining hepatic scavenger receptor, class B, type I (SR-BI) steady state levels but not its surface localization or function. J Biol Chem 281:28975-80
Karackattu, Sharon L; Trigatti, Bernardo; Krieger, Monty (2006) Hepatic lipase deficiency delays atherosclerosis, myocardial infarction, and cardiac dysfunction and extends lifespan in SR-BI/apolipoprotein E double knockout mice. Arterioscler Thromb Vasc Biol 26:548-54
Yesilaltay, Ayce; Kocher, Olivier; Rigotti, Attilio et al. (2005) Regulation of SR-BI-mediated high-density lipoprotein metabolism by the tissue-specific adaptor protein PDZK1. Curr Opin Lipidol 16:147-52
Karackattu, Sharon L; Picard, Michael H; Krieger, Monty (2005) Lymphocytes are not required for the rapid onset of coronary heart disease in scavenger receptor class B type I/apolipoprotein E double knockout mice. Arterioscler Thromb Vasc Biol 25:803-8
Zhang, Songwen; Picard, Michael H; Vasile, Eliza et al. (2005) Diet-induced occlusive coronary atherosclerosis, myocardial infarction, cardiac dysfunction, and premature death in scavenger receptor class B type I-deficient, hypomorphic apolipoprotein ER61 mice. Circulation 111:3457-64

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