Plasma HDL levels are inversely associated with the risk for atherosclerosis. The HDL or scavenger receptor-B1 (SR-B1) is a recently-described plasma membrane receptor for HDL that mediates the selective delivery of HDL cholesterol ester to cells. The principal investigator has shown that alternative splicing of SR-B1 mRNA occurs in man and mouse tissues, the relevance of which is unknown. SR-B1 has been mapped to a locus associated with HDL levels (unpublished observations). Inflammation induces a wide variety of metabolic changes and two of these in particular lead to modulation of HDL structure and metabolism. The induced acute phase serum amyloid A (SAA) displaces apolipoprotein A-I and markedly remodels the HDL particle. Another acute phase protein, secretory non-pancreatic phospholipase A2 (sPLA2) is concomitantly induced and can hydrolyze HDL phospholipids. The central hypothesis to be examined in this proposal is that the modification of HDL that occurs during inflammation leads to alterations in the interaction between HDL and SR-B1. Such changes would have important implications for HDL metabolism and could affect HDL-mediated cholesterol delivery to the liver as well as cholesterol flux between HDL and cells in localized atherosclerotic lesions.
The specific aims of this proposal are: 1) determine the significance of alternative mRNA splicing in the regulation and functional activity of SR-B1. This will be achieved by quantifying the expression of the different forms of SR-B1 mRNA and protein under conditions that regulate SR-B1 expression and by expressing the different forms of SR-B1 in cultured cells and comparing their abilities to function as HDL receptors; 2) determine how inflammation-induced modifications of HDL influence HDL binding to the SR-B1 receptor and selective lipid uptake into cells. This will be achieved by determining whether modifications of HDL during an acute phase response or modification by sPLA2 and SAA specifically, alters HDL binding to SR-B1 or SR-B1-mediated lipid delivery to cells; and 3) determine the extent to which SR-B1 expression in the mouse influences the plasma levels of normal and acute phase HDL. This will be achieved by determining the effect of adenovirus-mediated over-expression of SR-B1 on the levels of normal and acute phase HDL and of other lipoproteins.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL059376-01
Application #
2452612
Study Section
Physiological Chemistry Study Section (PC)
Project Start
1998-01-01
Project End
2000-12-31
Budget Start
1998-01-01
Budget End
1998-12-31
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Kentucky
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
832127323
City
Lexington
State
KY
Country
United States
Zip Code
40506
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Webb, Nancy R; Cai, Lei; Ziemba, Kristine S et al. (2002) The fate of HDL particles in vivo after SR-BI-mediated selective lipid uptake. J Lipid Res 43:1890-8
Webb, Nancy R; de Beer, Maria C; Yu, Jin et al. (2002) Overexpression of SR-BI by adenoviral vector promotes clearance of apoA-I, but not apoB, in human apoB transgenic mice. J Lipid Res 43:1421-8
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de Beer, M C; Durbin, D M; Cai, L et al. (2001) Apolipoprotein A-I conformation markedly influences HDL interaction with scavenger receptor BI. J Lipid Res 42:309-13
de Beer, M C; Durbin, D M; Cai, L et al. (2001) Apolipoprotein A-II modulates the binding and selective lipid uptake of reconstituted high density lipoprotein by scavenger receptor BI. J Biol Chem 276:15832-9
Goti, D; Hrzenjak, A; Levak-Frank, S et al. (2001) Scavenger receptor class B, type I is expressed in porcine brain capillary endothelial cells and contributes to selective uptake of HDL-associated vitamin E. J Neurochem 76:498-508
de Beer, F C; Connell, P M; Yu, J et al. (2000) HDL modification by secretory phospholipase A(2) promotes scavenger receptor class B type I interaction and accelerates HDL catabolism. J Lipid Res 41:1849-57
Matveev, S; van der Westhuyzen, D R; Smart, E J (1999) Co-expression of scavenger receptor-BI and caveolin-1 is associated with enhanced selective cholesteryl ester uptake in THP-1 macrophages. J Lipid Res 40:1647-54
Fluiter, K; Sattler, W; De Beer, M C et al. (1999) Scavenger receptor BI mediates the selective uptake of oxidized cholesterol esters by rat liver. J Biol Chem 274:8893-9

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