Recent evidence suggests that abnormalities in the metabolism of triglycerides and fatty acids are linked to the occurrence of premature coronary artery disease. In cells, fatty acids are used as a source of energy, as building blocks for membrane biogenesis, and as precursors for complex regulatory molecules such as eicosanoids and thromboxanes. The transport of fatty acids among plasma and the many cellular compartments is a highly regulated process that is made all the more complex by postprandial lipemia and the attendant lipolysis. A major theme of the BCM-SCOR is that abnormalities in triglyceride and fatty acid metabolism contribute to atherosclerosis. Since elevation in fatty acids can contribute increased secretion of very low density lipoprotein- triglycerides, fatty acid and triglyceride metabolism are directly connected. Acylation-stimulating protein (ASP or BP-1) is one of three recently described proteins that promote the intracellular accumulation of fatty acids and their subsequent conversion of triglycerides, particularly in peripheral tissue. The role that this protein plays in abnormal lipid metabolism and atherosclerosis is not known. The purpose of this project is to answer the following questions: 1] Is plasma ASP elevated in metabolic states where plasma triglycerides and free fatty acids are raised? 2] Does ASP bind to a cell-surface protein in those cells where its activity is expressed? 3] What intracellular enzymes of lipid synthesis are effected by ASP? 4] Does ASP play an essential physiological role? 5] What are the structures of the functional domains of ASP? These questions will be answered by in vivo studies in hamsters, immunocytochemistry, subcellular organelle isolation, digital imaging microscopy, quantitative lipid analysis, gas and liquid chromatography, immunoassays, peptide sequencing and synthesis and structural analysis. The long term goal of this project is to identify the role of acylation stimulating proteins in controlling the flux of fatty acids in plasma and cells and to determine if an abnormality in the function of this class of proteins is important in abnormal triglyceride metabolism nd atherogenesis.
