Alcoholic Liver Dysfunction Potentiation by Hyperlipidemia and Cigarette Smoke

描述(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，检验酒精性肝病分子机制的研究是使用模型进行的，其中遗传和环境背景不受在人类群体中观察到的流行的先前存在的病理或潜在的风险因素的影响。重要的是，这些模型没有在两个重要方面反映人类人口：1)普遍存在的高脂血症；2)普遍暴露在空气传播的环境毒物中，如二手烟烟雾。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，流行病学研究表明，高脂血症和香烟烟雾具有相加或协同作用，可以加重酒精性肝病。事实上，慢性酒精与其他共病危险因素对肝脏生理和损伤的联合影响仍不明确。因此，这项应用的目标是研究高脂血症背景下的ETS加速和放大酒精性肝损伤的分子途径和靶点。该项目建立在动物模型的新发现基础上，该模型揭示了酒精、香烟烟雾和高脂血症通过增强低氧和氧化/硝化应激而放大肝脏损伤的关键作用，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出来。支持这一观点的发现是：(1)暴露于酒精和ETS的小鼠线粒体DNA损伤最严重；(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。线粒体功能的一个新出现的方面是细胞器在关键的氧化还原信号通路中所起的作用，这些信号通路调节细胞对新陈代谢、低氧和氧化应激的反应。这些发现提出了一个具有挑衅性的假设，即线粒体功能缺陷扰乱了这些信号通路，并参与了酒精、肝脏毒性和环境侮辱(如ETS)的病理生理学。基于此，我们假设联合暴露于酒精、香烟烟雾和高脂血症会增加线粒体功能障碍和ROS产生，触发HIF1a的激活，这反过来又有助于放大脂肪变性。这一假说将在三个目标下进行检验：(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说；(2)确定酒精、吸烟和高脂血症对线粒体ROS/RNS产生和呼吸蛋白修饰的单独和联合影响；以及(3)检验线粒体ROS/RNS有助于酒精、香烟烟雾和高脂血症引起HIF1a激活和脂肪变性的假说。这些研究将揭示并机械地定义酒精与其他共病风险之间的相加或协同关系，如在酒精性肝病的病理生理学中，吸烟和高脂血症。 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。重要的是，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程度都在增加。近年来，情况也变得很清楚，其他既往存在的疾病，如2型糖尿病和高胆固醇，以及暴露在香烟烟雾等有毒物质中，都会加剧慢性酒精消费者的肝病。这项应用中的研究很重要，因为他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扮演什么角色？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): 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.