Coordination of hepatic fatty acid metabolism

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The balance of hepatic lipid synthesis, uptake, export and oxidation plays an important role in the progression and pathogenesis of the metabolic syndrome and is particularly important for the growing incidence of Nonalcoholic Steatohepatitis (NASH). However, the mechanisms governing the shift from normal metabolic physiology to pathophysiology are poorly understood, particularly with respect to the role of lipid metabolism. Our overall goal is to determine how the liver senses and responds to fluctuations in fatty acid availability to facilitate key processes such as gluconeogenesis and ketogenesis, and to understand how targeting lipid metabolism could either protect or potentiate obesity, diabetes and NASH. We have developed multiple mouse models that disrupt fatty acid catabolism at unique metabolic nodes in the liver. We have shown that although all of these models exhibit fatty liver and exist in a putative linear pathway for the oxidation of fatty acids, they exhibit surprisingly unique cellular and molecular phenotypes. These data demonstrate that both triglyceride hydrolysis and fatty acid oxidation convey unique biochemical information to the hepatocyte to coordinate the catabolism of fatty acids. To describe this unique fatty acid dependent regulatory code, we propose three specific aims to 1) Determine the independent roles for triglyceride hydrolysis and fatty acid oxidation during fasting, 2) Determine the independent and interdependent roles of triglyceride hydrolysis and fatty acid oxidation in HFD-induced obesity and 3) Determine the role of fatty acid-dependent lysine acetylation in the regulation of hepatic metabolism. Here we will use these models to understand the metabolic code by which fatty acids affect the hepatic coordination of lipid metabolism.