Aberrant BCAA utilization in alcohol-induced metabolic dysregulation

项目摘要 饮酒是第三大可预防的死亡原因，并带来显著的经济损失 在美国的负担。长期大量饮酒会增加代谢失调的风险， 如2型糖尿病、脂肪肝和心血管疾病，以及相关的过早死亡。 然而，人们还没有很好地理解大量饮酒是如何机械地产生的 与代谢紊乱的发生和发展有关。血液中分支的水平升高- 链氨基酸(支链氨基酸；缬氨酸、亮氨酸和异亮氨酸)与肥胖、2型糖尿病、 脂肪肝，以及啮齿动物和人类的心血管疾病。新出现的证据表明 棕色脂肪组织以热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改善胰岛素敏感性和糖耐量。我们的初步数据 提示慢性过量酒精可引起小鼠体内异常高水平的支链氨基酸蓄积 人原代棕色脂肪细胞。靶向基因表达分析提示支链氨基酸受损 利用机制包括线粒体支链氨基酸的运输、氧化和产热 慢性过量酒精刺激下的棕色脂肪细胞。在我们早期的动物研究中，循环增加 在酒精喂养的动物中，在生理水平上检测到支链氨基酸水平。因此，我们假设 长期过量饮酒会损害棕色脂肪介导的支链氨基酸的利用，进而 通过增加全身支链氨基酸的积累，导致酒精代谢失调。在体外和体内使用 活体系统与慢性过量酒精的挑战，我们将彻底表征异常棕色 与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 首次提供证据表明长期大量饮酒会损害生热脂肪的功能 BCAA的代谢下沉并扰乱能量平衡，这是 酒精引起的全身性代谢失调。因此，这项研究的结果将有助于 填补对酒精性组织损伤和依赖认识的现有知识空白 代谢性疾病和制定治疗策略以逆转广泛的酒精诱导的 代谢紊乱。

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.