The role of PDK4 in alcohol-associated liver disease

摘要 酒精相关性肝病(ALD)是一个主要的健康问题，可导致肝功能衰竭、肝癌和 死亡，在美国每年产生巨大的医疗支出。可用于治疗的特效药很少 ALD患者。在许多患者中，禁欲是很难实现的，而且不能阻止以后的进展 ALD分期。破译ALD的分子机制和识别新的标记可导致新的 这是一种治疗途径，对公共卫生和福利有很大的意义。线粒体，中心位置 对于酒精代谢酶来说，是酒精毒性反应的活性介体。线粒体改变 酒精诱导是ALD的一个标志，它对细胞代谢有深远的影响，并与 炎症的激活，是ALD发病的基础。丙酮酸脱氢酶4(PDK4) 使线粒体基质中的丙酮酸脱氢酶复合体(PDC)失活，从而抑制转换 丙酮酸转化为乙酰辅酶A。PDK4维持线粒体的动态平衡，参与了 非酒精性脂肪性肝病的发生和凋亡性肝损伤。然而，人们对这一角色知之甚少 PDK4在ALD中的表达。这项建议旨在揭示PDK4是如何通过激活线粒体来协调线粒体功能障碍的 面对酒精性肝损伤的炎症反应。我们的中心假设是PDK4功能的丧失 损害酒精代谢/解毒，增强促炎反应，促进发育 对ALD的影响。我们的目标是：(1)确定PDK4在酒精喂养小鼠肝损伤中的作用；(2)揭示PDK4在乙醇喂养的小鼠肝损伤中的作用。 PDK4在酒精性肝损伤中的分子机制。我们建议的研究将在概念上和 从机制上揭示了线粒体乙醇代谢和炎性小体激活之间的联系， 这有助于为ALD的治疗开辟新的治疗途径。此K01应用程序将允许 申请者通过整合跨学科资源获得ALD方面的高级知识和研究技能。 申请人已经组建了一个由杰出成员组成的咨询委员会，其中包括劳拉博士 Nagy(导师)、斯里尼瓦桑·达萨拉西和李晓霞，他们是著名的肝病专家或公认的 酒精代谢、炎症、线粒体生物学、基因表达和调控等领域的科学家， 免疫学等，具有培养初级科学家独立和成功研究的令人敬畏的记录 学术界。他们将指导申请人的学术生涯发展，并为 实施拟议的实验。

ABSTRACT Alcohol-associated liver disease (ALD) is a major health problem and can lead to liver failure, liver cancer, and death, incurring enormous healthcare expenditures annually in the US. Few specific treatments are available for patients with ALD. Abstinence is difficult to achieve in many patients and cannot prevent the progression at later stages of ALD. Deciphering molecular mechanisms and identifying novel markers of ALD can lead to new therapeutic avenues and is of substantial interest to public health and welfare. Mitochondria, the central location for alcohol-metabolizing enzymes, are active mediators in response to alcohol toxicity. Mitochondrial alterations induced by alcohol are a hallmark of ALD, which have profound impacts on cell metabolism and associate with activation of inflammation, underlying the pathogenesis of ALD. Pyruvate dehydrogenase kinase 4 (PDK4) inactivates pyruvate dehydrogenase complex (PDC) in the mitochondrial matrix, thus suppressing the conversion of pyruvate to acetyl-CoA. PDK4 maintains mitochondrial homeostasis and has been implicated in the development of non-alcoholic fatty liver disease and apoptotic liver injury. However, little is known about the role of PDK4 in ALD. This proposal is to reveal how PDK4 coordinates mitochondrial dysfunction with activation of inflammation in the face of ethanol-induced liver injury. Our central hypothesis is that loss of PDK4 function impairs alcohol metabolism/detoxification and enhances pro-inflammatory response to promote the development of ALD. We aim to: (1) define the role PDK4 in liver injury in mouse models of ethanol feeding; (2) unravel the molecular mechanisms of PDK4 in ethanol-induced liver injury. Our proposed studies will conceptually and mechanistically reveal the connection between mitochondrial ethanol metabolism and inflammasome activation, which helps to open novel therapeutic avenues for the treatment of ALD. This K01 application will allow the applicant to acquire advanced knowledge and research skills in ALD by integrating interdisciplinary resources. The applicant has assembled an advisory committee composed of outstanding members, including Drs. Laura Nagy (mentor), Srinivasan Dasarathy, and Xiaoxia Li, who are renowned hepatologists or well-recognized scientists in fields of alcohol metabolism, inflammation, mitochondrial biology, gene expression and regulation, immunology, etc., with a formidable record of training junior scientists to be independent and successful in academia. They will direct the applicant's academic career development and provide full support to the implementation of proposed experiments.