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 SR-B1 has been mapped to a locus associated with HDL levels (unpublished observations).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.
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