Aberrant BCAA utilization in alcohol-induced metabolic dysregulation

酒精引起的代谢失调中支链氨基酸的异常利用

• 批准号: 10730925
• 负责人: Heejin Jun
• 金额: $ 48.2万
• 依托单位: TEXAS TECH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10730925
• 关键词: Adipocytes; Adipose tissue; Affect; Alcohol consumption; Alcohols; Amino Acids; Animal Feed; Animals; Blood; Branched-Chain Amino Acids; Brown Fat; Cardiovascular Diseases; Cells; Cessation of life; Chronic; Data; Defect; Development; Dose; Economic Burden; Energy Metabolism; Enzymes; Ethanol; Exposure to; Fatty acid glycerol esters; Gene Expression Profiling; Generations; Genetic; Heavy Drinking; Human; Impairment; In Vitro; Isoleucine; Isotopes; Knowledge; Leucine; Mediating; Metabolic; Metabolic Diseases; Metabolic dysfunction; Mitochondria; Modeling; Molecular; Mus; National Institute on Alcohol Abuse and Alcoholism; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome Study; Oxygen Consumption; Pathologic; Phenotype; Physiological; Process; Proteins; RNA; Radiolabeled; Regimen; Risk; Rodent; Series; System; Testing; Therapeutic; Thermogenesis; Time; Tissues; United States; Valine; blood glucose regulation; energy balance; fatty liver disease; feeding; gain of function; glucose tolerance; improved; in vivo; insulin sensitivity; loss of function; mortality; mouse model; oxidation; pharmacologic; premature; problem drinker

Project Summary Alcohol consumption is the third leading preventable cause of mortality and carries a significant economic burden in the United States. Chronic heavy alcohol drinking increases the risk of metabolic dysregulation, such as type 2 diabetes, fatty liver disease, and cardiovascular disease, and related premature death. However, what has not been well understood is how heavy alcohol consumption is mechanistically associated with the onset and progression of metabolic disorders. Increased blood levels of Branched- Chain Amino Acids (BCAA; valine, leucine, and isoleucine) are associated with obesity, type 2 diabetes, fatty liver disease, and cardiovascular disease in both rodents and humans. Emerging evidence suggests that brown adipose tissue that dissipates excess energy in the form of heat actively utilizes BCAA and improves insulin sensitivity and glucose tolerance through systemic BCAA clearance. Our preliminary data indicated that chronic excessive alcohol caused abnormally highly accumulated BCAA levels in mouse and human primary brown adipocytes. Targeted gene expression analysis suggested impairment of BCAA utilization machinery encompassing mitochondrial BCAA transport, oxidation, and thermogenesis in primary brown adipocytes upon chronic excessive alcohol challenge. In our early animal study, elevated circulating BCAA levels were detected in alcohol-fed animals at the physiological level. Accordingly, we hypothesize that chronic excessive alcohol drinking impairs brown adipose-mediated BCAA utilization, which in turn causes alcoholic metabolic dysregulation via increased systemic BCAA accumulation. Using in vitro and in vivo systems with chronic excessive alcohol challenges, we will thoroughly characterize abnormal brown cellular phenotypes associated with BCAA utilization (Aim 1) and their mechanisms (Aim 2) in a cell- autonomous manner and validate the in vitro findings at the physiological level (Aim 3). Our study will provide the first evidence that chronic heavy alcohol drinking damages thermogenic fat function as a metabolic sink for BCAA and disturbs energy balance, which serves as a pathological mechanism for alcohol-induced systemic metabolic dysregulation. Therefore, the outcome of this study will contribute to filling the existing knowledge gap in understanding alcohol-induced tissue damage and dependent metabolic diseases and developing a therapeutic strategy to reverse a broad range of alcohol-induced metabolic disorders.

项目摘要 饮酒是死亡率的第三个主要可预防原因，并带有大量经济 在美国的负担。慢性大量饮酒会增加代谢失调的风险， 例如2型糖尿病，脂肪肝病和心血管疾病以及相关的早期死亡。 但是，尚未充分理解的是，饮酒方式是如何机械化的 与代谢性疾病的发作和进展相关。分支的血液水平增加 链氨基酸（BCAA； Valine，Leucine和Isoleucine）与肥胖症，2型糖尿病有关 啮齿动物和人类的脂肪肝病和心血管疾病。新兴证据表明 以热的形式耗散多余能量的棕色脂肪组织积极利用BCAA和 通过全身性BCAA清除来提高胰岛素敏感性和葡萄糖耐受性。我们的初步数据 表明慢性饮酒导致小鼠和 人类原发性棕色脂肪细胞。靶向基因表达分析表明BCAA受损 利用机械包括线粒体BCAA转运，氧化和产生的原发性机制 棕色脂肪细胞在慢性饮酒挑战中。在我们早期的动物研究中，循环升高 在生理水平的酒精喂养动物中检测到BCAA水平。因此，我们假设 长期过度饮酒会损害棕色脂肪介导的BCAA利用率，这反过来又 通过增加全身性BCAA积累引起酒精代谢失调。在体外和使用 慢性酒精挑战的体内系统，我们将彻底表征异常棕色 与BCAA利用率（AIM 1）及其机制（AIM 2）相关的细胞表型 自主方式并验证生理水平的体外发现（AIM 3）。我们的研究愿意 提供第一个证据，表明慢性重酒精饮酒会损害热脂肪作为一种 BCAA的代谢水槽和打扰能量平衡，这是一种病理机制 酒精诱导的全身代谢失调。因此，这项研究的结果将有助于 填补现有的知识差距，以理解酒精引起的组织损害和依赖 代谢疾病并制定一种治疗策略，以扭转广泛的酒精诱导 代谢障碍。