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

阐明肝脏 mTORC2 作为碳水化合物代谢关键调节因子在非酒精性脂肪肝中的作用

• 批准号: 10387520
• 负责人: John Anthony Haley
• 金额: $ 3.4万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10387520
• 关键词: ATP Citrate (pro-S)-Lyase; Ablation; Acetates; Acetyl Coenzyme A; Acute; Address; Affect; American; Auxins; Brown Fat; Carbohydrates; Cells; Cirrhosis; Complex; Consumption; Developed Countries; Developing Countries; Diet; Dose; Endocrine; Enzymes; FDA approved; FRAP1 gene; Fasting; Fatty Liver; Fatty acid glycerol esters; Fructose; Gluconeogenesis; Glucose; Glycogen; Goals; Hepatic; Hepatocyte; High Fat Diet; Homeostasis; Human; Impairment; Lead; Life Style; Link; Lipids; Liver; Metabolic; Metabolic Diseases; Metabolism; Modernization; Molecular Biology; Mus; Nuclear; Nutrient; Obesity; Organ; Pathogenesis; Pathologic; Pathology; Pathway interactions; Persons; Phosphorylation; Plants; Prevalence; Primary carcinoma of the liver cells; Process; Production; Proteomics; Regulation; Role; Signal Transduction; System; Testing; Time; Work; base; carbohydrate metabolism; clinically relevant; cost; dietary supplements; fighting; flexibility; lipid biosynthesis; lipid metabolism; liver transplantation; metabolomics; neglect; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel therapeutics; protective effect; response; standard of care; sugar

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.

项目总结