Alcohol Metabolism Disrupts Hepatic Thiol Redox Signaling and Control

项目摘要 饮酒约占全球死亡人数的6%，是发病率的主要原因。 以及美国境内的死亡率。这些统计数据表明，迫切需要了解 酒精毒性的生化机制及酒精性肝病的发病机制 (ALD)。慢性酒精代谢影响许多细胞途径，包括糖酵解、脂肪代谢、 三氯乙酸循环以及抗氧化剂和炎症反应。已知的生物化学联系在 代谢变化、氧化应激和蛋白质硫醇氧化还原开关(如半胱氨酸残基)； 然而，关于慢性酒精代谢如何影响肝脏硫醇氧化还原的信息很少。 信令和控制网络。我们的初步数据支持酒精代谢、蛋白质 乙酰化和半胱氨酸氧化还原是高度相关的。因此，我们提出了一种创新的方法来 研究酒精代谢如何影响硫醇氧化还原信号和控制。硫醇是我们目标的核心 氧化还原蛋白质组是一种适应性界面，它提供了一种感知、避免和防御氧化剂的方法 和其他毒物。因此，这一提议的假设是酒精代谢影响硫醇氧化还原 通过赖氨酸乙酰化的信号和控制，导致肝脏动态平衡失调，并参与ALD。 我们将研究提出的特定目标来检验我们的假设：特定目标1：表征改变的硫醇 酒精代谢引起的氧化还原信号和控制。具体目标2：利用Sirtuin 1过度表达 定义乙酰化-氧化还原信号和控制的机制。具体目标3：整合氧化还原机制-- Cys和乙酰赖氨酸来阐明CoAlation特异的氧化还原信号。我们将执行这些研究目标 利用前沿蛋白质组学和生物信息学方法揭示新的氧化还原传感机制 在肝细胞内。阐明酒精代谢如何改变肝脏氧化还原信号和控制 新的翻译后修饰将支持开发有针对性的临床干预措施 改善数百万美国人的阿尔茨海默病。

Project Summary Alcohol consumption contributes to approximately 6% of worldwide deaths and is a major cause of morbidity and mortality within the United States. These statistics support a pressing need for understanding the biochemical mechanisms underlying alcohol toxicity and the pathogenesis of alcohol-associated liver disease (ALD). Chronic alcohol metabolism impacts numerous cellular pathways including glycolysis, lipid metabolism, the TCA cycle as well as antioxidant and inflammatory responses. There is a known biochemical link between metabolic alterations, oxidative stress, and protein thiol redox switches (e.g., cysteine (Cys) residues); however, very little information exists regarding how chronic alcohol metabolism impacts hepatic thiol redox signaling and control networks. Our preliminary data supports the notion that alcohol metabolism, protein acetylation, and Cys redox are highly associated. Therefore, we present an innovative approach for investigating how alcohol metabolism impacts thiol redox signaling and control. Central to our aims, the thiol redox proteome is an adaptive interface that provides a means to sense, avoid, and defend against oxidants and other toxicants. Therefore, the hypothesis of this proposal is that alcohol metabolism impacts thiol redox signaling and control through lysine acetylation, resulting in hepatic dyshomeostasis and contributing to ALD. We will investigate the proposed specific aims to test our hypothesis: Specific Aim 1: Characterize altered thiol redox signaling and control due to alcohol metabolism. Specific Aim 2: Utilize Sirtuin 1 overexpression to define mechanisms of acetylation-redox signaling and control. Specific Aim 3: Integrate mechanisms of redox- Cys and acetyl-Lys to elucidate CoAlation specific redox signaling. We will execute these research aims utilizing a cutting-edge proteomics and bioinformatics approach to reveal novel redox sensing mechanisms within hepatocytes. Elucidating how alcohol metabolism alters hepatic redox signaling and control through novel post-translational modifications will support the development of targeted clinical interventions to ameliorate ALD in millions of Americans.