The scavenger receptor-BI (SR-BI) has recently been characterized as the high-density lipoprotein (HDL) receptor. SR-BI is a plasma membrane receptor that binds HDL and mediates the selective uptake of cholesteryl ester from HDL and HDL-dependent cholesterol efflux from cells. It is expressed in a variety of cells and tissues important in lipoprotein metabolism and atherosclerosis, such as macrophages and the liver, and is present in the atherosclerotic plaque. Preliminary studies indicate that alcohol regulates SR-Bl expression. There are as yet no human studies describing the regulation of this receptor nor have any genetic abnormalities been found that affect SR-Bl function. This proposal seeks to examine the effects of alcohol on the role of the SR-BI receptor in HDL metabolism. Moderate alcohol consumption may further lessen the risk of atherosclerosis by modulation of HDL structure and metabolism leading to a decrease in its anti-atherogenic properties. These changes may include i) alterations in apolipoprotein A-I and A-II content, and ii) alterations in paraoxonase activity on HDL particles.This proposal seeks to examine the molecular basis for the alterations in HDL levels and properties which occur in human experimental models of moderate alcohol consumption. Our specific objective are: 1) to determine the extent to which alcohol regulates SR-Bl expression and SR-BI mediated lipid flow. This will be accomplished by quantifying the effects of alcohol on i) the extent of alternative mRNA splicing of SR-BI, ii) the expression of the different forms of SR-Bl, and iii) the ability of SR-Bl to function as HDL receptors and to mediate selective lipid uptake into cells and cholesterol efflux from cells. This will be done in human cell culture systems. 2) to determine the effects of alcohol on apolipoprotein A-I and A-II composition of HDL particles and efficiency of SR-BI mediated selective uptake of cholesterol ester. This will be done by characterizing A-I and A-II content of HDL from human subjects exposed to alcohol and determining the relative efficiency of their HDL particles to deliver cholesterol ester to SR-BI transfected cells via selective uptake.3) to characterize the effects of alcohol on the protective anti-oxidative capacity of HDL. This will be done by measuring the bioactivity of paraoxonase and determining the ability of HDL from human subjects exposed to alcohol to protect against macrophage-mediated LDL.
