Hepatocyte Clock and Alcoholic Fatty Liver Injury

描述(申请人提供)：慢性和过度饮酒是美国可预防的死亡的第三大原因，有200万美国人患有酒精性肝病。与许多疾病一样，酒精性肝病的病因是复杂的，是多种基因-环境-代谢相互作用和紊乱的产物。例如，酒精依赖的多个信号通路的失调导致脂肪生成增加，减少脂肪酸氧化和肝脏中过量的脂肪积累。众所周知，长期饮酒也会改变昼夜节律行为；这些行为直接受到昼夜节律的调节，这些节律存在于几乎所有哺乳动物细胞中，包括中央(视交叉上核，SCN)和外周(肝脏)组织的细胞。环境和基因对时钟调节途径的破坏都会导致生物体与其环境的去同步，以及器官/组织之间的去同步，导致细胞功能障碍和病理。器官间去同步化是否进而导致酒精性组织损伤尚不清楚。因此，这项提议的目标是研究慢性乙醇扰乱生物钟导致肝脏脂肪变性和损伤的分子途径和靶点。这一建议建立在新的发现基础上，即心肌细胞生物钟直接调节心肌甘油三酯的周转，在小鼠活动期结束时将脂肪酸引导到甘油三酯合成中。与这些观察的心脏外意义一致的是，在活动期结束时喂食高脂饮食会导致肥胖、高胰岛素血症和高甘油三酯血症，这些都与每天的总卡路里数量无关。由于这些代谢紊乱可由慢性酒精摄入引起，并与脂肪变性有关，我们认为肝细胞生物钟调节肝脏甘油三酯代谢，酒精消耗的时间可能显著影响肝脏脂肪变性的发展。因此，我们的长期目标是调查慢性乙醇诱导的脂肪变性和肝功能障碍是否部分归因于中枢(SCN)时钟和肝脏(肝细胞)时钟之间的昼夜节律不同步。最初需要询问的两个问题包括：(1)长期饮酒是否导致SCN和肝脏之间的昼夜节律不同步，以及(2)肝细胞生物钟是否直接影响酒精诱导的肝脏甘油三酯代谢和脂肪变性的改变？突显这种跨学科R21应用的高风险和高影响性质的事实是，这些研究的目标是解决以前没有受到挑战的假设，即大脑和肝脏之间的昼夜不同步显著导致酒精性肝损伤。到目前为止，旨在确定慢性酒精消费对肝功能(和病理)的影响的研究忽略了人类酒精消费的时间性。这些拟议目标的完成可能会突出生物钟作为影响乙醇诱导的肝脏病理的一种新的分子机制。 与公共健康相关：在美国，酗酒被认为是导致可预防死亡的第三大原因。新的研究报告说，在美国，各种原因引起的肝病的患病率和严重性都在不断增加。近年来也变得明显的是，长期饮酒扰乱了肝细胞中的许多亚细胞代谢途径，这些被破坏的过程有助于疾病的发展。这项应用中的研究很重要，因为他们将试图回答这个问题：在慢性酒精消费者中，其他代谢因素在肝病恶化中扮演了什么角色？具体地说，这项研究项目将研究细胞昼夜节律或时钟在酒精性肝病中的作用。这一领域的研究将帮助医学专业人员更好地了解肝病的原因，并导致发现治疗与糖尿病、肥胖、丙型肝炎和酒精中毒相关的肝病患者的新方法。

DESCRIPTION (provided by applicant): Chronic and excessive alcohol consumption is the third leading cause of preventable death in the US with two million Americans afflicted with alcoholic liver disease. Like many diseases, the etiology of alcoholic liver disease is complex and a product of multiple gene-environment-metabolic interactions and disturbances. For example, alcohol-dependent dysregulation of multiple signaling pathways leads to increased lipogenesis, decreased fatty acid oxidation and excess lipid accumulation in liver. Chronic alcohol consumption is also known to alter circadian behavior; these behaviors are directly regulated by circadian clocks, which are present in virtually all mammalian cells including those of the central (suprachiasmatic nucleus, SCN) and peripheral (liver) tissues. Both environmental and genetic disruption of clock-mediated pathways results in desynchronization of an organism with its environment, as well as desynchrony between organs/tissues, resulting in cellular dysfunction and pathology. Whether inter-organ desynchrony, in turn, contributes to alcoholic tissue injury is not known. Accordingly, this proposal has the goal of investigating the molecular pathways and targets through which chronic ethanol disrupts circadian clocks leading to hepatic steatosis and injury. This proposal builds on new findings that the cardiomyocyte circadian clock directly regulates myocardial triglyceride turnover, channeling fatty acids into triglyceride synthesis at the end of the active period in mice. Consistent with the extra-cardiac significance of these observations, feeding mice a high fat diet specifically at the end of the active period results in adiposity, hyperinsulinemia, and hypertriglyceridemia, which are independent of total daily caloric quantity. As these same metabolic derangements can result from chronic ethanol consumption and are linked to steatosis, we propose that the hepatocyte circadian clock regulates liver triglyceride metabolism and that the time-of-day at which ethanol is consumed may markedly influence the development of hepatic steatosis. Thus, our long-term goal is to investigate whether chronic ethanol-induced steatosis and liver dysfunction are due, in part, to circadian desynchrony between the central (SCN) clock and the liver (hepatocyte) clock. Two initial questions that require interrogation include: (1) does chronic ethanol consumption cause circadian desynchrony between the SCN and liver, and (2) does the hepatocyte circadian clock directly influence ethanol-induced alterations in liver triglyceride metabolism and steatosis? Underscoring the high risk and high impact nature of this inter-disciplinary R21 application, is the fact that these studies have the goal to address a previously unchallenged hypothesis that circadian desynchrony between the brain and liver significantly contributes towards alcoholic liver injury. To date, studies designed to determine the impact of chronic ethanol consumption on liver function (and pathology) have ignored the temporal nature of ethanol consumption in humans. Completion of the proposed aims will likely highlight the circadian clock as a novel molecular mechanism influencing ethanol-induced liver pathology. PUBLIC HEALTH RELEVANCE: Alcohol abuse is estimated to be the third leading cause of preventable death in the United States. New studies report an increasing prevalence and severity of liver diseases from all causes in the United States. It has also become clear in recent years that chronic alcohol consumption disrupts many sub-cellular metabolic pathways in liver cells and that these disrupted processes contribute to the development of disease. The studies in this application are important as they will attempt to answer the question: What are the roles of other metabolic factors in worsening liver disease in the chronic alcohol consumer? Specifically, this research project will study the role of cellular circadian rhythms or clocks in alcoholic liver disease. Research in this area will help medical professionals better understand the causes of liver disease and lead to the discovery of new treatments for patients suffering from liver diseases associated with diabetes, obesity, hepatitis C, and alcoholism.