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.

项目概要 Non-alcoholic fatty liver disease (NAFLD) currently effects around 30% of Americans and costs the U.S 每年约1030亿美元。然而，护理标准仍然是改变生活方式和肝脏 目前尚无 FDA 批准的疗法进行移植。 NAFLD 通常与不断上升的肥胖相关 在发达国家和发展中国家。雷帕霉素复合物 2 (mTORC2) 的哺乳动物靶标正在出现 作为碳水化合物和脂质代谢的中心枢纽，其激活与 NAFLD 相关 老鼠。这些最近的研究强调了 mTORC2 调节在小鼠高脂肪饮食期间的作用， 其中肝脏 mTORC2 消融对高脂肪诱导的肝脂肪变性具有保护作用。 然而，对人类 NAFLD 发病率影响最大的膳食补充剂是 碳水化合物，特别是果糖。而 mTORC2 消融对高脂饮食期间肝脏的保护作用 尽管人们对饮食进行了研究，但它对高碳水化合物饮食的影响却被忽视了。在这里，我将检查 mTORC2 能够防止高碳水化合物诱导的肝脂肪变性，正如之前所研究的那样 在高脂肪饮食的背景下出现。从机制上讲，我将研究肝脏 mTORC2 的作用 调节碳水化合物衍生的乙酰辅酶A的合成和利用，从而促进发病机制 非酒精性脂肪肝病。我将通过检查两种不同的乙酰辅酶A产生酶来实现这一目标：ACLY和ACSS2。 我不仅将研究 mTORC2 通过磷酸化调节 ACLY 和 ACSS2 的作用，而且 同样是第一次，使用生长素降解决定子系统研究急性环境中 mTORC2 的丢失，这是一个 基于植物的内源降解标签。随着这项拟议工作的完成，我坚信 将获得对肝脏信号传导和代谢的更详细和机制的了解，从而提供 最终可用于治疗 NAFLD 和其他代谢性疾病的目标。