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：
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
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/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

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

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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主要原因。迄今为止，使用模型进行了检查酒精性肝病的分子机制的研究，在该模型中，遗传和环境背景不受普遍存在的先前病理或在人类种群中观察到的潜在危险因素的影响。重要的是，这些模型在两个重要方面并不反映人类种群：1）广泛的高脂血症和2）普遍暴露于空中环境有毒物质（例如二手香烟烟雾），又称环境烟草烟雾（ETS）。这很重要，因为这些危险因素是普遍存在的流行病学研究表明，高脂血症和香烟烟雾对加剧酒精性肝病具有累加或协同作用。实际上，慢性酒精与其他合并症风险因素对肝生理和损伤的综合作用仍然很差。因此，该应用的目的是研究分子途径和靶标的ETS在高脂血症加速的背景下通过该途径，并放大了酒精性肝损伤。该项目建立在动物模型中的新发现的基础上，该发现揭示了酒精，香烟烟雾和高脂血症的关键作用，可以通过增强的低氧和氧化/硝化应激来扩增肝损伤，这都具有线粒体的参与。确实，在这些研究过程中，已经出现了线粒体功能障碍的核心作用。支持此的结果是：（1）暴露于酒精和ET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iNOS和氧化蛋白的修饰，导致功能丧失。线粒体功能的最近出现和新颖的方面是细胞器在关键的氧化还原信号通路中所扮演的角色，该途径调节细胞对代谢，低氧和氧化应激的反应。这些发现提出了一个挑衅的假设，即线粒体功能的缺陷破坏了这些信号通路，并有助于酒精肝毒性和ETS等环境损害的病理生理学。基于此，我们假设暴露于酒精，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的激活，这又有助于扩大脂肪变性。该假设将以三个目的进行检验：（1）测试酒精，香烟烟雾和高脂血症会增加线粒体功能障碍并促进线粒体通透性过渡的假设；（2）确定酒精，香烟烟雾和高脂血症对线粒体ROS/RNS产生的单个和综合作用以及对呼吸蛋白的修饰；（3）检验了线粒体ROS/RNS的假设有助于HIF1A激活和脂肪变性，从酒精，香烟烟雾和高脂血症中造成了脂肪性疾病。这些研究将揭示并从机理上定义酒精与其他合并症风险（如香烟烟雾和高脂血症）在酒精性肝病病理生理学中的添加或协同关系。公共卫生相关性：估计酗酒是美国可预防死亡的第三主要原因。重要的是，新研究报告说，美国各种原因的肝病的患病率和严重程度越来越严重。近年来，近年来，其他现有的医疗状况（如2型糖尿病和高胆固醇）以及暴露于毒物（如香烟烟雾）中可能会使慢性酒精消费者的肝病恶化。本应用中的研究很重要，因为他们将尝试回答以下问题：其他环境和代谢因素在慢性酒精消费者中恶化的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病的原因，并为患有糖尿病，肥胖症，肝炎和酒精中毒的肝病患者发现新疗法。