Alcoholic Liver Dysfunction Potentiation by Hyperlipidemia and Cigarette Smoke

高脂血症和吸烟加剧酒精性肝功能障碍

• 批准号: 7932863
• 负责人: SHANNON MARIE BAILEY
• 金额: $ 30.82万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7932863
• 关键词: Alcohol Hepatotoxicity; Alcohol abuse; Alcohol dependence; Alcoholic Liver Diseases; Alcoholism; Alcohols; American; Animal Model; Apolipoprotein E; Area; Bioenergetics; Cessation of life; Chemosensitization; Cholesterol; Chronic; Comorbidity; DNA Damage; Defect; Development; Diabetes Mellitus; Diet; Environmental Tobacco Smoke; Epidemiologic Studies; Exposure to; Failure; Fatty Liver; Functional disorder; Genes; Genetic; Goals; Hand; Health; Heavy Drinking; Hepatic; Hepatitis C; Human; Hyperlipidemia; Hypoxia; Individual; Injury; Investigation; Lead; Link; Liver; Liver Dysfunction; Liver diseases; Medical; Metabolic; Mitochondria; Mitochondrial DNA; Mitochondrial Proteins; Modeling; Modification; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organ; Organelles; Oxidation-Reduction; Oxidative Stress; Pathology; Pathway interactions; Patients; Permeability; Physiology; Play; Population; Post-Translational Protein Processing; Prevalence; Production; Proteins; Proteome; Proteomics; Reporting; Research; Research Proposals; Respiratory Chain; Risk; Risk Factors; Role; Severities; Signal Pathway; Signal Transduction; Stress; Testing; Toxic Environmental Substances; Up-Regulation; alcohol effect; alcohol exposure; alcohol response; base; chronic alcohol ingestion; cigarette smoking; cytochrome c oxidase; dietary control; feeding; human SOD2 protein; liver function; loss of function; mitochondrial dysfunction; mouse model; novel; oxidative damage; problem drinker; public health relevance; research study; respiratory protein; response; toxicant

DESCRIPTION (provided by applicant): Excessive alcohol consumption is the third leading cause of preventable death in the US. To date, studies that examine the molecular mechanisms of alcoholic liver disease are performed using models in which the genetic and environmental backgrounds are unaffected by prevalent pre-existing pathologies or underlying risk factors observed in human populations. Importantly, these models do not reflect human populations in two important aspects: 1) widespread hyperlipidemia and 2) pervasive exposure to airborne environmental toxicants like second-hand cigarette smoke, a.k.a. environmental tobacco smoke (ETS). This is important because these risk factors are ubiquitous and epidemiologic studies show that hyperlipidemia and cigarette smoke have additive or synergistic effects to exacerbate alcoholic liver disease. Indeed, the combined effect of chronic alcohol with other co-morbidity risk factors on hepatic physiology and injury remains poorly defined. Accordingly, this application has the goal of investigating the molecular pathways and targets through which ETS on a background of hyperlipidemia accelerates and amplifies alcoholic liver injury. This project builds on new findings in an animal model, which reveals a critical role of alcohol, cigarette smoke, and hyperlipidemia to amplify liver injury via enhanced hypoxic and oxidative/nitrative stress, which all have mitochondrial involvement. Indeed, in the course of these studies a central role for mitochondrial dysfunction has emerged. Findings in support of this are: (1) Mitochondrial DNA damage is highest in mice exposed to alcohol and ETS; (2) Alcohol and ETS decrease cytochrome c oxidase protein and activity; and (3) Alcohol and ETS increase liver iNOS and oxidative protein modifications leading to a loss of function. A recently emerging and novel aspect of mitochondrial function is the role the organelle plays in key redox signaling pathways, which regulate cellular responses to metabolic, hypoxic, and oxidative stress. These findings raise the provocative hypothesis that defects in mitochondrial function disrupt these signaling pathways and contribute to the pathophysiology of alcohol hepatotoxicity and environmental insults like ETS. Based on this, we hypothesize that combined exposure to alcohol, cigarette smoke, and hyperlipidemia increases mitochondrial dysfunction and ROS production triggering activation of HIF1a, which in turn contributes to amplify steatosis. This hypothesis will be tested in three aims: (1) Test the hypothesis that alcohol, cigarette smoke, and hyperlipidemia increase mitochondrial dysfunction and promote the mitochondrial permeability transition; (2) Determine the individual and combined effects of alcohol, cigarette smoke, and hyperlipidemia on mitochondrial ROS/RNS production and modifications to respiratory proteins; and (3) Test the hypothesis that mitochondrial ROS/RNS contribute to HIF1a activation and steatosis from alcohol, cigarette smoke, and hyperlipidemia. These studies will reveal and mechanistically define the additive or synergistic relationship between alcohol and other co-morbidity risks like cigarette smoke and hyperlipidemia in the pathophysiology of alcoholic liver disease. PUBLIC HEALTH RELEVANCE: Alcohol abuse is estimated to be the third leading cause of preventable death in the US. Importantly, new studies report an increasing prevalence and severity of liver diseases from all causes in the US. It has also become clear in recent years that other pre-existing medical conditions like type 2 diabetes and high cholesterol along with exposure to toxicants like cigarette smoke can worsen liver disease in the chronic alcohol consumer. The studies in this application are important as they will attempt to answer the question: What are the roles of other environmental and metabolic factors in worsening liver disease in the chronic alcohol consumer? 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）：过量饮酒是美国可预防死亡的第三大原因。到目前为止，研究酒精性肝病的分子机制是使用遗传和环境背景不受流行的预先存在的病理或在人群中观察到的潜在风险因素影响的模型进行的。重要的是，这些模型在两个重要方面没有反映人群：1）广泛的高脂血症和2）普遍暴露于空气传播的环境毒物，如二手香烟烟雾，也称为环境烟草烟雾（ETS）。这一点很重要，因为这些危险因素普遍存在，流行病学研究表明，高脂血症和吸烟具有加重酒精性肝病的叠加或协同作用。事实上，慢性酒精与其他共病风险因素对肝脏生理和损伤的综合影响仍然很难确定。因此，本申请的目标是研究在高脂血症背景下的ETS通过其加速和放大酒精性肝损伤的分子途径和靶标。该项目建立在动物模型中的新发现的基础上，该模型揭示了酒精，香烟烟雾和高脂血症通过增强缺氧和氧化/硝化应激放大肝损伤的关键作用，这些都涉及线粒体。事实上，在这些研究的过程中，线粒体功能障碍的核心作用已经出现。支持这一点的发现是：（1）暴露于酒精和ETS的小鼠中线粒体DNA损伤最高;（2）酒精和ETS降低细胞色素c氧化酶蛋白和活性;（3）酒精和ETS增加肝脏iNOS和氧化蛋白修饰，导致功能丧失。线粒体功能的一个最近出现的和新的方面是细胞器在关键的氧化还原信号通路中发挥的作用，其调节细胞对代谢、缺氧和氧化应激的反应。这些发现提出了一个挑衅性的假设，即线粒体功能缺陷会破坏这些信号通路，并导致酒精肝毒性和环境损伤（如ETS）的病理生理学。基于此，我们假设酒精、香烟烟雾和高脂血症的联合暴露增加了线粒体功能障碍和ROS产生，触发HIF 1a的激活，这反过来又有助于放大脂肪变性。该假设将在三个目标中进行检验：（1）检验酒精、香烟烟雾和高脂血症增加线粒体功能障碍并促进线粒体通透性转换的假设;（2）确定酒精、香烟烟雾和高脂血症对线粒体ROS/RNS产生和呼吸蛋白修饰的单独和组合影响;以及（3）检验线粒体ROS/RNS有助于HIF 1a活化和酒精、香烟烟雾和高脂血症引起的脂肪变性的假设。这些研究将揭示并从机制上定义酒精与其他共病风险（如吸烟和高脂血症）在酒精性肝病病理生理学中的相加或协同关系。 公共卫生相关性：据估计，酒精滥用是美国可预防死亡的第三大原因。重要的是，新的研究报告了美国各种原因引起的肝病的患病率和严重程度不断增加。近年来，人们也越来越清楚，其他预先存在的医疗条件，如2型糖尿病和高胆固醇沿着暴露于香烟烟雾等有毒物质，会使慢性酒精消费者的肝脏疾病恶化。本申请中的研究很重要，因为它们将试图回答这个问题：其他环境和代谢因素在慢性酒精消费者肝脏疾病恶化中的作用是什么？该领域的研究将帮助医疗专业人员更好地了解肝脏疾病的原因，并为患有与糖尿病、肥胖、丙型肝炎和酗酒相关的肝脏疾病的患者发现新的治疗方法。