Abstract

HDL levels are inversely related to coronary artery disease. The HDL receptor, SR-BI, plays a key role in HDL metabolism. SR-BI binds HDL and mediates the process known as selective lipid uptake, the mechanism of which is not understood. Various studies have indicated that selective uptake by SR-BI in certain cells occurs at the cell surface by a non-endocytic process. However, recent studies have reported that in hepatocytes SR-BI mediates the internalization of intact HDL particles and suggest that selective lipid uptake involves HDL internalization and recycling in cells. We have shown that SR-BII, a variant of SR-BI, differs markedly from SR-BI in its cellular trafficking and endocytosis of HDL. The central hypothesis of this proposal is that the functions of SR-BI and SR-BII in intracellular cholesterol trafficking are coupled to receptor/ligand recycling in cells and that SR-BI and SR-BII follow different internalization and recycling routes and differentially affect cellular cholesterol trafficking and regulation.
The specific aims are: 1) determine the contribution of HDL internalization and intracellular recycling to the selective lipid uptake process mediated by SR-BI and SR-BII. HDL recycling by each of the two receptors will be quantified in hepatocytes and other cells, 2) elucidate the mechanisms responsible for HDL internalization and recycling by SR-BI and SR-BII. Endocytic and recycling pathway(s) used by SR-BI and SR-BII will be studied and protein motifs in the C-terminal tails of SR-BI and SR-BII that are responsible for receptor targeting will be identified, 3) determine how differences in the intracellular targeting of HDL by SR-BI and SR-BII influence cellular cholesterol regulation and trafficking. We will determine the effects of selective lipid uptake via SR-BI and SR-BII on the pool of regulatory sterols in cells and on cholesterol efflux and 4) assess the roles of SR-BI and SR-BII in HDL metabolism and atherogenesis in vivo using isoform-specific knock-in mice. Isoform-specific knock-in mice will be generated and the effects of each receptor on plasma lipoproteins, HDL metabolism and atherogenesis studied. ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL063763-07
Application #
7267833
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Srinivas, Pothur R
Project Start
1999-12-01
Project End
2009-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
7
Fiscal Year
2007
Total Cost
$309,348
Indirect Cost

  Institution

Name
University of Kentucky
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506

  Publications

Cai, Lei; Ji, Ailing; de Beer, Frederick C et al. (2008) SR-BI protects against endotoxemia in mice through its roles in glucocorticoid production and hepatic clearance. J Clin Invest 118:364-75
Sun, Bing; Boyanovsky, Boris B; Connelly, Margery A et al. (2007) Distinct mechanisms for OxLDL uptake and cellular trafficking by class B scavenger receptors CD36 and SR-BI. J Lipid Res 48:2560-70
van der Westhuyzen, Deneys R; de Beer, Frederick C; Webb, Nancy R (2007) HDL cholesterol transport during inflammation. Curr Opin Lipidol 18:147-51
Cai, Zhaohui; Cai, Lei; Jiang, Jieyun et al. (2007) Human serum amyloid A protein inhibits hepatitis C virus entry into cells. J Virol 81:6128-33
Shetty, Shoba; Eckhardt, Erik R M; Post, Steven R et al. (2006) Phosphatidylinositol-3-kinase regulates scavenger receptor class B type I subcellular localization and selective lipid uptake in hepatocytes. Arterioscler Thromb Vasc Biol 26:2125-31
Sun, Bing; Eckhardt, Erik R M; Shetty, Shoba et al. (2006) Quantitative analysis of SR-BI-dependent HDL retroendocytosis in hepatocytes and fibroblasts. J Lipid Res 47:1700-13
Pagler, Tamara A; Rhode, Sebastian; Neuhofer, Angelika et al. (2006) SR-BI-mediated high density lipoprotein (HDL) endocytosis leads to HDL resecretion facilitating cholesterol efflux. J Biol Chem 281:11193-204
van der Westhuyzen, Deneys R; Cai, Lei; de Beer, Maria C et al. (2005) Serum amyloid A promotes cholesterol efflux mediated by scavenger receptor B-I. J Biol Chem 280:35890-5
Cai, Lei; de Beer, Maria C; de Beer, Frederick C et al. (2005) Serum amyloid A is a ligand for scavenger receptor class B type I and inhibits high density lipoprotein binding and selective lipid uptake. J Biol Chem 280:2954-61
Zhao, Zhenze; de Beer, Maria C; Cai, Lei et al. (2005) Low-density lipoprotein from apolipoprotein E-deficient mice induces macrophage lipid accumulation in a CD36 and scavenger receptor class A-dependent manner. Arterioscler Thromb Vasc Biol 25:168-73

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