This application represents a continuation of a Program Project whose overall theme is the metabolism of lipids, cholesterol and lipoproteins as related to the development of atherosclerosis. The interactions of lipoproteins with cells and tissues and the subsequent metabolism of lipids within cells will be investigated. The basic information that will be gained is particularly relevant to understanding the protective action of high density lipoprotein (HDL) against premature coronary artery disease and the progression and regression of atherosclerotic plague. The major emphasis of this research focuses on: 1) relationships between cellular lipid metabolism and the assembly and secretion of lipid-protein complexes, 2) cellular uptake, metabolism and release of lipids, and 3) the role of apolipoprotein (apo) conformation in determining the structures and functions of lipoprotein particles. This Program Project consists of four closely related projects: Project 1 proposes to study the effects of fish oil fatty acids on lipoprotein metabolism. Emphasis is on factors regulating hepatic assembly and secretion of apo B-containing lipoproteins. Project 2 represents a continuation of studies on the flux of cholesterol between lipoproteins and cells in culture. Emphasis is placed on establishing the mechanism(s) and regulation of movement of cholesterol between HDL and cultured cells. Project 4 extends previous work on the structure of lipoproteins to a study of the conformations and lipid-binding properties of apolipoproteins to better understand the structures of different species of HDL particles. Project 6 focuses on the intracellular metabolism of free and esterified cholesterol, using macrophages as model foam cells. Emphasis is placed on the factors involved in the deposition and clearance of esterified cholesterol from these cells. The group of investigators comprising this Program Project share similar interests and goals in lipid and lipoprotein metabolism while providing broad scientific expertise. The scientific disciplines encompassed by these investigators include biochemistry, physiology, physical chemistry, cell and molecular biology and nutrition. The four scientific projects are supported by two core laboratories: 1) Tissue Culture Core and 2) Lipoprotein Core.
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