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

基本信息

批准号：
7798912
负责人：
SHANNON MARIE BAILEY
金额：
$ 31.12万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
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/7798912
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 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 Morbidity - disease rate 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

项目摘要

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。迄今为止，检查酒精性肝病分子机制的研究是使用遗传和环境背景不受人群中普遍存在的病理或潜在危险因素影响的模型进行的。重要的是，这些模型没有反映人群的两个重要方面：1）广泛的高脂血症和2）普遍接触空气传播的环境毒物，如二手烟烟雾，又称环境烟草烟雾（ETS）。这一点很重要，因为这些危险因素无处不在，而且流行病学研究表明，高脂血症和吸烟具有叠加或协同作用，可加剧酒精性肝病。事实上，长期饮酒与其他合并症危险因素对肝脏生理和损伤的综合影响仍然不明确。因此，本申请的目的是研究高脂血症背景下 ETS 加速和放大酒精性肝损伤的分子途径和靶标。该项目基于动物模型的新发现，揭示了酒精、香烟烟雾和高脂血症通过增强缺氧和氧化/硝化应激而放大肝损伤的关键作用，而这些都与线粒体有关。事实上，在这些研究过程中，线粒体功能障碍的核心作用已经显现。支持这一点的发现包括：(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 会增加肝脏 iNOS 和氧化蛋白修饰，导致功能丧失。线粒体功能最近出现的一个新方面是细胞器在关键氧化还原信号通路中发挥的作用，该通路调节细胞对代谢、缺氧和氧化应激的反应。这些发现提出了一个令人兴奋的假设，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 ETS 等环境损害的病理生理学。基于此，我们假设同时接触酒精、香烟烟雾和高脂血症会增加线粒体功能障碍和 ROS 产生，从而触发 HIF1a 激活，进而导致脂肪变性加剧。该假设将在三个目标上进行检验：（1）检验酒精、吸烟和高脂血症会增加线粒体功能障碍并促进线粒体通透性转变的假设； (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综合影响； (3) 检验线粒体 ROS/RNS 有助于酒精、香烟烟雾和高脂血症引起的 HIF1a 激活和脂肪变性的假设。这些研究将揭示并从机制上定义酒精与酒精性肝病病理生理学中吸烟和高脂血症等其他共病风险之间的累加或协同关系。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。重要的是，新的研究报告称，在美国，各种原因引起的肝脏疾病的患病率和严重程度都在不断增加。近年来，人们已经清楚地知道，其他已有的疾病，如 2 型糖尿病和高胆固醇，以及接触香烟烟雾等有毒物质，可能会加重长期饮酒者的肝病。本申请中的研究很重要，因为它们将试图回答以下问题：其他环境和代谢因素在慢性饮酒者肝病恶化中发挥什么作用？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。