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: 10548816
• 负责人: John Anthony Haley
• 金额: $ 3.49万
• 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/10548816
• 关键词: ATP Citrate (pro-S)-Lyase; Ablation; Acetates; Acetyl Coenzyme A; Acute; Address; Affect; American; Auxins; Brown Fat; Carbohydrates; Cells; Cirrhosis; Communication; Complex; Consumption; Cytoplasm; 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; 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; 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.

项目摘要 非酒精性脂肪性肝病(NAFLD)目前影响着大约30%的美国人，并使美国 每年约1,030亿美元。然而，护理的标准仍然是改变生活方式和肝脏 目前没有FDA批准的治疗方法的移植。非酒精性脂肪肝通常与不断上升的肥胖症相关 在发达国家和发展中国家都是如此。雷帕霉素复合体2(MTORC2)的哺乳动物靶点正在出现 作为碳水化合物和脂肪代谢的中心枢纽，其激活已与 老鼠。这些最近的研究强调了mTORC2在小鼠高脂饮食中的调节作用， 肝脏mTORC2消融术对高脂诱导的肝脏脂肪变性有保护作用。 然而，最能归因于人类NAFLD上升的膳食补充剂是 碳水化合物，特别是果糖。MTORC2消融对高脂大鼠肝脏的保护作用 饮食已有研究，其对高碳水化合物饮食的影响一直被忽视。在这里，我将研究 MTORC2预防高碳水化合物诱导的肝脏脂肪变性的能力，正如以前所做的那样 可以在高脂肪饮食的背景下看到。从机制上讲，我将研究肝脏mTORC2 调节碳水化合物衍生的乙酰辅酶A的合成和利用，从而促进发病 非酒精性脂肪肝。我将通过检测两种不同的乙酰辅酶A产生酶来实现这一点：ACLY和ACSS2。 我不仅将研究mTORC2的S在通过磷酸化调控ACLY和ACSS2中的作用，而且 也是第一次，使用生长素降解系统在急性情况下调查mTORC2丢失，这是一种 植物内源降解标签。随着这项拟议工作的完成，我坚信 将获得对肝脏信号和代谢的更详细和更机械的理解，为 最终可用于治疗非酒精性脂肪肝和其他代谢性疾病的靶点。