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.

项目概要 饮酒是第三大可预防的死亡原因，并带来重大的经济影响 美国的负担。长期大量饮酒会增加代谢失调的风险， 例如 2 型糖尿病、脂肪肝、心血管疾病以及相关的过早死亡。 然而，目前尚不清楚的是，大量饮酒的机制是怎样的？ 与代谢紊乱的发生和进展有关。血液中支链的水平增加 链氨基酸（BCAA；缬氨酸、亮氨酸和异亮氨酸）与肥胖、2 型糖尿病、 啮齿动物和人类的脂肪肝疾病和心血管疾病。新出现的证据表明 棕色脂肪组织以热量的形式消耗多余的能量，积极利用支链氨基酸和 通过全身支链氨基酸清除提高胰岛素敏感性和葡萄糖耐量。我们的初步数据 表明长期过量饮酒会导致小鼠和小鼠的 BCAA 水平异常升高 人原代棕色脂肪细胞。靶向基因表达分析表明支链氨基酸受损 初级利用机制包括线粒体支链氨基酸运输、氧化和产热 慢性过量酒精挑战后的棕色脂肪细胞。在我们早期的动物研究中，循环升高 在酒精喂养的动物中检测到生理水平的支链氨基酸水平。据此，我们假设 长期过量饮酒会损害棕色脂肪介导的 BCAA 利用率，从而反过来 通过增加全身 BCAA 积累导致酒精代谢失调。体外和体内使用 体内系统与慢性过量酒精挑战，我们将彻底表征异常棕色 与细胞中支链氨基酸利用相关的细胞表型（目标 1）及其机制（目标 2） 自主方式并在生理水平上验证体外研究结果（目标 3）。我们的研究将 提供了第一个证据，证明长期大量饮酒会损害生热脂肪的功能 BCAA 的代谢库并扰乱能量平衡，这是一种病理机制 酒精引起的全身代谢失调。因此，本研究的结果将有助于 填补了了解酒精引起的组织损伤和依赖性方面的现有知识空白 代谢疾病并制定治疗策略以逆转广泛的酒精诱发的疾病 代谢紊乱。