Elucidating the role of hepatic mTORC2 as a key regulator of carbohydrate metabolism in non-alcoholic fatty liver disease

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Project Summary Non-alcoholic fatty liver disease (NAFLD) currently effects around 30% of Americans and costs the U.S approximately $103 billion annually. However, the standard of care remains lifestyle changes and liver transplantation with currently no FDA approved therapies. NAFLD often correlates with obesity which is rising in both developed and developing nations. Mammalian target of rapamycin complex 2 (mTORC2) is emerging as a central hub for carbohydrate and lipid metabolism, with its activation having been linked to NAFLD in mice. These recent studies have highlighted a role for mTORC2 modulation during high-fat diets in mice, where hepatic mTORC2 ablation provides a protective effect against high-fat induced hepatic steatosis. However, the dietary supplements that have been most attributed to the rise of NAFLD in humans are carbohydrates, specifically fructose. While protective effects of mTORC2 ablation in the liver during high-fat diet have been investigated, its impact on high-carbohydrate diets has been neglected. Here, I will examine the ability for mTORC2 to protect against high-carbohydrate induced hepatic steatosis, as has previously been seen in the context of high-fat diets. Mechanistically, I will investigate the role by which hepatic mTORC2 regulates carbohydrate derived acetyl-CoA synthesis and utilization, subsequently promoting the pathogenesis of NAFLD. I will accomplish this by examining two distinct acetyl-CoA producing enzymes: ACLY and ACSS2. Not only will I investigate mTORC2’s role in regulating both ACLY and ACSS2 through phosphorylation, but also for the first time, investigate mTORC2 loss in an acute setting using an auxin degron system, which is a plant based endogenous degradation tag. With the completion of this proposed work, I strongly believe that a more detailed and mechanistic understanding of hepatic signaling, and metabolism will be obtained, providing targets which could ultimately be used to treat NAFLD and other metabolic diseases.