Hepatocyte Clock and Alcoholic Fatty Liver Injury

肝细胞时钟与酒精性脂肪肝损伤

• 批准号: 8065283
• 负责人: SHANNON MARIE BAILEY
• 金额: $ 21.98万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-20 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8065283
• 关键词: Address; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholic Fatty Liver; Alcoholic Liver Diseases; Alcoholism; Alcohols; American; Animal Model; Area; Behavior; Biochemical; Brain; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cells; Cessation of life; Chronic; Circadian Rhythms; Complex; Development; Diabetes Mellitus; Diet; Disease; Dyslipidemias; Environment; Enzymes; Ethanol; Etiology; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Functional disorder; Genes; Genetic; Glucose Intolerance; Goals; Health; Heavy Drinking; Hepatitis C; Hepatocyte; Human; Hyperinsulinism; Hypertriglyceridemia; Injury; Knockout Mice; Lead; Link; Lipids; Liver; Liver Dysfunction; Liver diseases; Luciferases; Mammalian Cell; Measures; Mediating; Medical; Metabolic; Metabolic Pathway; Molecular; Mus; Myocardial; Nature; Nuclear Receptor Gene; Obesity; Organ; Organism; Pathogenesis; Pathology; Pathway interactions; Patients; Peripheral; Phase; Prevalence; Process; Reporting; Research; Research Design; Research Project Grants; Research Proposals; Role; Severities; Signal Pathway; Stimulus; Syndrome; Testing; Time; Tissues; Triglyceride Metabolism; Triglycerides; United States; alcohol exposure; chronic alcohol ingestion; circadian pacemaker; dietary control; extracellular; fatty acid oxidation; feeding; high risk; lipid biosynthesis; liver function; mouse model; novel; problem drinker; public health relevance; suprachiasmatic nucleus

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.

描述（由申请人提供）：长期过量饮酒是美国可预防死亡的第三大原因，有 200 万美国人患有酒精性肝病。与许多疾病一样，酒精性肝病的病因很复杂，是多种基因-环境-代谢相互作用和紊乱的产物。例如，多种信号通路的酒精依赖性失调会导致脂肪生成增加、脂肪酸氧化减少以及肝脏中脂质过度积累。众所周知，长期饮酒也会改变昼夜节律行为。这些行为直接受到生物钟的调节，生物钟几乎存在于所有哺乳动物细胞中，包括中枢（视交叉上核，SCN）和外周（肝脏）组织的细胞。时钟介导途径的环境和遗传破坏都会导致生物体与其环境不同步，以及器官/组织之间的不同步，从而导致细胞功能障碍和病理。器官间不同步是否反过来会导致酒精组织损伤尚不清楚。因此，该提案的目标是研究长期乙醇扰乱生物钟导致肝脂肪变性和损伤的分子途径和靶点。该提议建立在新发现的基础上，即心肌细胞生物钟直接调节心肌甘油三酯周转，在小鼠活动期结束时将脂肪酸引导至甘油三酯合成。与这些观察结果的心脏外意义一致，特别是在活动期结束时给小鼠喂食高脂肪饮食会导致肥胖、高胰岛素血症和高甘油三酯血症，这些与每日总热量无关。由于这些相同的代谢紊乱可能是由慢性乙醇消耗引起的，并且与脂肪变性有关，因此我们认为肝细胞生物钟调节肝脏甘油三酯代谢，并且消耗乙醇的时间可能显着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央（SCN）时钟和肝脏（肝细胞）时钟之间的昼夜节律不同步。需要询问的两个初步问题包括：（1）慢性乙醇消耗是否会导致视交叉上核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乙醇引起的肝脏甘油三酯代谢和脂肪变性的改变？强调这一跨学科 R21 应用的高风险和高影响性的事实是，这些研究的目标是解决一个先前未经质疑的假设，即大脑和肝脏之间的昼夜节律不同步显着导致酒精性肝损伤。迄今为止，旨在确定长期乙醇消耗对肝功能（和病理学）影响的研究忽略了人类乙醇消耗的时间性质。完成所提出的目标可能会凸显生物钟作为影响乙醇诱导的肝脏病理学的新型分子机制。 公共卫生相关性：据估计，酗酒是美国可预防死亡的第三大原因。新的研究报告称，在美国，各种原因引起的肝病的患病率和严重程度都在不断增加。近年来，人们已经清楚，长期饮酒会破坏肝细胞中的许多亚细胞代谢途径，而这些被破坏的过程会导致疾病的发展。本申请中的研究很重要，因为它们将试图回答以下问题：其他代谢因素在慢性饮酒者肝病恶化中发挥什么作用？具体来说，该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。该领域的研究将帮助医疗专业人员更好地了解肝病的原因，并为患有与糖尿病、肥胖、丙型肝炎和酗酒相关的肝病的患者找到新的治疗方法。