Function and Regulation of GPIHBP1 in Lipid Metabolism

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The main objective of Project 1 ("Function and Regulation of GPIHBP1 in Lipid Metabolism") is to define the function of glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1) in plasma triglyceride metabolism and in the regulation of fuel delivery to adipose tissue and muscle. This objective is closely aligned with the overall objectives of this PPG, which are to elucidate the basic mechanisms of triglyceride metabolism and adipogenesis, focusing on newly discovered molecules and pathways that are regulated by PPARy. Gpihbpl-deficient mice have severe chylomicronemia, even on a low-fat diet, with plasma triglyceride levels as high as 5000 mg/dl. GPIHBP1 is located on the luminal surface of endothelial cells of heart, muscle, and fat, where lipolysis of plasma triglycerides occurs. Expression of GPIHBP1 in cultured cells confers the ability to bind both lipoprotein lipase (LpL) and chylomicrons, suggesting that GPIHBP1 is a key platform for the lipolytic processing of chylomicrons along the luminal face of capillaries. Although GPIHBP1 is clearly important for the lipolysis of triglyceride-rich lipoproteins, many issues regarding the biological function of GPIHBP1 have not been explored. We have not yet examined the impact of different diets on lipid and glucose metabolism in Gpihbpl-deficient mice, nor do we know why Gpihbpl - deficient mice are protected from diet-induced obesity. Also, the molecular basis for chylomicron and LpL binding to GPIHBP1 is unknown¿in particular whether the highly negatively charged domain in GPIHBP1 interacts with positively charged "heparin-binding" domains in LpL and various apolipoproteins within chylomicrons (e.g., apo-E, apo-B, and apo-AV). Finally, Gpihbpl is highly regulated by fasting and refeeding and by PPARy, but the molecular basis for this regulation has not been defined. In Specific Aim 1, we will further define the metabolic abnormalities in Gpihbpl-deficient mice. In Specific Aim 2, we will identify the structural domains of GPIHBP1 required for the binding of LpL and chylomicrons and define the apolipoproteins that mediate the binding of chylomicrons (and other lipoprotein fractions) to Gpihbpl-transfected cells. In Specific Aim 3, we will define the tissue pattern of Gpihbpl expression and changes in Gpihbpl expression with PPARy agonists and different metabolic conditions.