The goal of the proposed research is to determine the role of plasma lipoproteins in the extracellular accumulation of lipids in the arteries and aorta. Our efforts will be directed toward the study of the factors influencing the activities of lecithin- cholesterol acyltransferase lipid transfer protein and the nature of their involvement in the metabolism and transport of cholesterol and cholesterol esters in the circulation. Since the enzymatic reaction may facilitate the transfer of free cholesterol from aortic tissues to high density lipoproteins, the enzyme is potentially an important factor in preventing lipid accumulation. The cholesterol esters produced by the enzymatic reaction are rapidly equilibrated among various plasma lipoproteins by lipid transfer protein. Thus, a close functional interrelationship exists between the enzyme and this carrier protein in determining the fate of cholesterol in the circulation . We will attempt to clarify: 1) the effects of various apolipoproteins in the lecithin-cholesterol acyltransferase reaction, 2) the properties of lipid transfer protein and its interaction with plasma lipoproteins and lipid particles, 3) the factors influencing the formation and distribution of cholesterol esters in plasma, and 4) the hepatic metabolism of HDL cholesterol esters and triglycerides. The first phase of study is to provide basic information on the molecular mechanisms of the activation and inhibition of the enzymatic reaction by various apolipoproteins. The second phase of study is concerned with the characterization of lipid transfer protein and the nature of its interaction with plasma lipoproteins. In the third phase of study, the interrelationship of the enzymatic and lipid transfer reactions will be emphasized. The last phase of study will investigate the hepatic uptake of the cholesterol esters produced by lecithin-cholesterol acyltransferase and remaining in HDL, as well as the cleavage of the triglycerides transferred to HDL by hepatic triglyceride lipase. Human plasma will be primarily used for the separation of lecithin-cholesterol acyltransferase, lipid transfer protein, and plasma lipoproteins. The hepatic metabolism of HDL cholesterol esters and triglycerides will be investigated by using perfused rat liver and cultured rat hepatocytes. Through the proposed study, we hope to formulate a detailed scheme illustrating the roles of lecithin-cholesterol acyltransferase and lipid transfer protein in the transport of cholesterol from peripheral tissues to the liver.
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