Circadian and mitochondrial dysfunction in alcohol-related liver disease

项目摘要 酒精相关性肝病（ALD）是长期和过量饮酒导致死亡的头号原因 在美国酒精肝毒性的一个早期和主要靶点是胆固醇。慢性酒精 消耗严重损害肝脏线粒体生物能量功能;然而，特定的分子 线粒体损伤的机制还不清楚。我们也不知道完整的 线粒体功能障碍在ALD病理生物学中的贡献。越来越多的证据表明 一种被称为分子生物钟的内在生物学机制调节器官如何对 外部环境因素，以及内部生理刺激和异常病理应激。那里 越来越多的证据表明，昼夜节律被长期饮酒所扰乱，这可能导致 基因突变或时钟基因缺失会增加代谢功能障碍和肝脏病理， 酒精模型根据这个科学前提，我们发现长期饮酒会显著降低肝脏 时钟振幅并扰乱肝脏时钟的定时。肝脏特异性Bmal 1缺失的酒精喂养小鼠 表现出葡萄糖和糖原代谢节律受损，肝脏甘油三酯脂质组失调， 与饲喂酒精饮食的对照基因型小鼠相比，肝脏疾病病理学评分更高。我们也有 令人兴奋的新的初步数据显示，慢性酒精显着抑制和破坏的节奏， 肝线粒体生物能量功能，包括限速酶细胞色素c氧化酶的活性 线粒体呼吸作用。基于这些令人兴奋的新观察，我们提供了一个新的范式， 在慢性饮酒期间线粒体生物能量功能的昼夜节律控制中， 在ALD发病机制中的作用。我们将通过三个具体目标来检验这一假设。在目标1中，我们 确定慢性饮酒破坏了肝脏线粒体生物能量功能的24小时节律。 在目的2中，我们将明确肝细胞BMAL 1和E4 BP 4在酒精诱导的线粒体生物能量代谢中的作用。 功能障碍和肝损伤。在目标3中，我们将测试在饮酒期间恢复肝脏生物钟活动是否可以防止 线粒体功能障碍和肝损伤。这些结果将提供第一个洞察之间的关系， 昼夜节律系统和酒精对线粒体生物能量学和器官损伤的影响。项目结果将有 通过推进刺激药物发现所需的临床前科学知识产生直接转化影响 在用于治疗患有ALD的患者的基于线粒体和时间生物学的疗法领域， 其他严重的肝脏疾病。

PROJECT SUMMARY Alcohol-related liver disease (ALD) is the number one cause of death from long-term and excessive alcohol use in the United States. One early and primary target of alcohol hepatotoxicity is the mitochondrion. Chronic alcohol consumption severely compromises liver mitochondrial bioenergetic function; however, the specific molecular mechanisms responsible for mitochondrial damage are not well understood. We also do not know the full contribution of mitochondrial dysfunction in pathobiology of ALD. Accumulating evidence supports the concept that an intrinsic biological mechanism known as the molecular circadian clock regulates how organs respond to external environmental factors, as well as internal physiological stimuli and abnormal pathologic stresses. There is a growing body of evidence that circadian rhythms are disrupted by chronic alcohol use, which likely contribute to disease as genetic mutation or deletion of clock genes increase metabolic dysfunction and liver pathology in alcohol models. Regarding this scientific premise, we discovered that chronic alcohol significantly deceases liver clock amplitude and disrupts the timing of the liver clock. Alcohol-fed mice with liver-specific deletion of Bmal1 exhibit impaired glucose and glycogen metabolism rhythms, a dysregulated hepatic triglyceride lipidome, and a greater liver disease pathology score compared to control genotype mice fed an alcohol diet. We also have exciting new preliminary data showing chronic alcohol significantly dampens and disrupts rhythmicity of critical hepatic mitochondrial bioenergetic functions, including activity of cytochrome c oxidase, the rate-limiting enzyme of mitochondrial respiration. Building on these exciting new observations, we offer a new paradigm where loss in circadian control of mitochondrial bioenergetic function during chronic alcohol consumption plays a key causal role in the pathogenesis of ALD. We will test this hypothesis through three Specific Aims. In Aim 1, we will establish that chronic alcohol consumption disrupts 24-h rhythms in hepatic mitochondrial bioenergetic function. In Aim 2, we will define the roles of hepatocyte BMAL1 and E4BP4 in alcohol-induced mitochondrial bioenergetic dysfunction and liver injury. In Aim 3, we will test if reinstating liver clock activity during alcohol use prevents mitochondrial dysfunction and liver injury. These results will provide the first insights into the relationship between the circadian system and alcohol on mitochondrial bioenergetics and organ damage. Project findings will have direct translational impact by advancing pre-clinical scientific knowledge required for stimulating drug discovery in the areas of mitochondrial and chronobiology based therapeutics for treating patients afflicted with ALD and other serious liver diseases.