The long-term goals of our research are to understand how hepatic glycerolipid synthesis contributes to disorders like obesity, diabetes, atherosclerosis, and how triacylglycerol synthesis is regulated. The proposed studies for this renewal focus primarily on the role, requirement, structure and function of the initial and committed step in the pathway of triacylglycerol synthesis, the acylation of sn-glycerol-3-P by glycerol-3- phosphate acyltransferase (GPAT). Our recent data, provided by over-expression studies and studies in knockout mice, suggest that the mitochondrial GPAT isoform (mtGPAT) 1) directs exogenous fatty acids towards triacylglycerol synthesis and away from oxidation and 2) directly controls the amount of palmitate in the sn-1 position of glycerolipids and indirectly controls the amount of arachidonate at the sn-2 position. These findings have implications regarding obesity, insulin resistance and eicosanoid production. We will determine 1) how mtGPAT is regulated by phosphorylation; 2) how mtGPAT knockout mice are protected against insulin resistance and obesity 3) whether mtGPAT and CPT-1 directly compete for acyI-CoAs at the mitochondrial membrane; and 4) what the consequence of absent mtGPAT is in hepatocytes, inflammatory cells and brain. Answers to these questions will allow us to understand how mtGPAT functions in cells to partition acyI-CoAs towards glycerolipid synthesis and away from beta-oxidation, how cells regulate their triacylglycerol content, and what the implications are for the normal positioning of fatty acids in glycerolipids. The information gained could lead to advances in the therapy of disorders characterized by abnormal regulation of VLDL synthesis or triacylglycerol storage.
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