Hepatic mTORC1 Signaling and the Regulation of Lipid Homeostasis

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Disorders associated with altered lipid metabolism such as non-alcoholic fatty liver disease (NAFLD) and atherosclerosis are a significant health threat to the U.S. population. As result, it is imperative to define the molecular mechanisms driving abnormal lipid homeostasis to identify new and effective therapeutics. Insulin- resistance is one of the most significant risk factors for lipid dysfunction; however, significant knowledge gaps remain in our understanding of how abnormal insulin action leads to altered lipid metabolism in metabolic disease. The liver is responsible for regulating the rates of lipid production and breakdown to control systemic lipid homeostasis. Dysregulation of these processes underly the pathogenesis of dyslipidemia and NAFLD, the latter consisting of a spectrum of liver diseases that encompasses simple liver steatosis (NAFL) and non- alcoholic steatohepatitis (NASH). Work by several laboratories including ours have implicated liver insulin signaling via the AKT-mTORC1 pathway in the regulation of lipid metabolism. Recent work from our laboratory uncovered a novel function for liver mTORC1 signaling in the regulation of phospholipid metabolism that is essential for the proper control of both hepatic and systemic lipid levels by insulin. This discovery has important implications to NAFLD and dyslipidemia and adds significant mechanistic insight into the role of insulin signaling via mTORC1 in the regulation of lipid metabolism. In Aim 1 of this proposal, we will build on these important observations and define the molecular mechanism underlying mTORC1's control of phosphatidylcholine biosynthesis and hepatic lipid homeostasis. In Aim 2, we will explore the therapeutic potential of manipulating liver mTORC1 signaling in the initiation and progression of NAFLD using multiple models of NASH. Collectively, this proposal will build upon recent discoveries regarding the role of insulin signaling via mTORC1 in the regulation of hepatic lipid metabolism. These experiments have the potential to significantly affect our mechanistic understand of the metabolic pathways that connect abnormal insulin signaling to NAFLD and dyslipidemia, which will provide the foundation for new therapeutic targets for fatty liver disease and pro- atherogenic dyslipidemia.