Dissecting the Role of Unfolded Protein Response in Alcoholic Liver Disease

剖析未折叠蛋白反应在酒精性肝病中的作用

• 批准号: 8240830
• 负责人: Ling Qi
• 金额: $ 18.29万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-10 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8240830
• 关键词: 1,2-diacylglycerol; Acetyltransferase; Acute; Adenoviruses; Adult; Affect; Alcohol consumption; Alcoholic Fatty Liver; Alcoholic Intoxication; Alcoholic Liver Diseases; Alcoholism; Alcohols; American; Animal Model; Binding; Binding Proteins; Biogenesis; CCAAT-Enhancer-Binding Proteins; Cellular Structures; Chronic; Cirrhosis; Clinical; Collaborations; Cues; Data; Developed Countries; Development; Diabetes Mellitus; Diglycerides; Drug Delivery Systems; Drug Metabolic Detoxication; Embryonic Development; Endoplasmic Reticulum; Enzymes; Fatty Liver; Fibrosis; Figs - dietary; Genes; Genetic; Goals; Health; Heavy Drinking; Hepatic; Hepatitis; Homeostasis; Human; Hypertension; Injury; Intervention; Lead; Link; Lipids; Lipoproteins; Liver; Liver Cirrhosis; Liver diseases; Malignant Neoplasms; Mediating; Metabolic; Methodology; Methods; Modeling; NADH; Non-Insulin-Dependent Diabetes Mellitus; Oxidoreductase; Pathogenesis; Pathway interactions; Patients; Physiological; Play; Population; Primary carcinoma of the liver cells; Proteins; Recruitment Activity; Regulation; Regulatory Element; Reporting; Risk; Role; Severities; Signal Pathway; Signal Transduction; Site; Staging; Sterols; Stress; System; Testing; Therapeutic; Time; Tissues; Tropism; United States; Work; alcohol research; alcohol response; base; binge drinker; binge drinking; biological adaptation to stress; cell type; chromatin immunoprecipitation; chronic alcohol ingestion; chronic liver disease; drinking; endoplasmic reticulum stress; feeding; forging; gain of function; insight; lipid biosynthesis; lipid metabolism; loss of function; mouse model; novel; prevent; problem drinker; programs; promoter; response; small hairpin RNA; stearoyl-coenzyme A; tool; transcription factor; treatment strategy

DESCRIPTION (provided by applicant): Alcoholism threatens the health of millions of Americans in the United States. Alcoholic fatty liver disease, or steatosis, is one of the earliest and most common consequences of excess alcohol consumption and can lead to more severe forms of liver injury, including cirrhosis, diabetes, hepatitis, fibrosis and hepatocellular carcinoma. Therefore, understanding the pathogenesis of alcohol-induced fatty liver disease is of great clinical and basic importance. Recent studies have suggested that response to stress in the endoplasmic reticulum (ER), or unfolded protein response (UPR) may be involved in the pathogenesis of alcoholic liver disease. This is a very attractive model because the ER is the predominant site for lipid biosynthesis, lipid droplet biogenesis, and alcohol detoxification, and because hepatic ER has been reported to expand in alcoholics. However, the causal relationship between ER stress and alcoholic fatty liver has yet to be established. We and others have recently shown that the IRE11-XBP1 branch of the UPR pathway plays a critical role in lipid metabolism. Excitingly, our preliminary data reveal that acute alcohol challenge doubled the activity of IRE11 in the liver within minutes, suggesting that ER stress occurs at an early stage following alcohol consumption. Moreover, ER stress was observed in two chronic-binge drinking mouse models with more severe forms of liver injury. Hence, the goal of this R21 proposal is to delineate the role of the IRE11-XBP1 branch in the pathogenesis of alcoholic fatty liver disease. We hypothesize that the IRE11-XBP1 branch of UPR directly regulates the lipogenic program in the liver in response to chronic-binge alcohol drinking, thereby playing a key role in the pathogenesis of alcoholic fatty liver disease. This hypothesis identifies the IRE11-XBP1 branch and ER homoeostasis as key components linking chronic-binge alcohol drinking and alcoholic fatty liver disease. Using state of the art methodology (e.g. adenoviral shRNA to achieve gene- and liver-specific temporal knockdown, Phos-tag-based method to quantitate ER stress under physiological conditions and tissue ChIP-qPCR to quantitate the binding of a transcription factor to specific gene promoters in the liver), we will test this hypothesis with the following Aims: (1) To determine how modulation of the IRE11-XBP1 pathway affects the pathogenesis of alcoholic fatty liver; (2) To explore the fundamental mechanism by which the IRE11-XBP1 pathway regulates lipogenic genes in response to alcohol. If successful, this study will establish, for the first time to our knowledge, a causal relationship between the UPR and alcoholic fatty liver disease. Relevance to human health: Excessive alcohol intake is a leading cause of chronic liver disease worldwide. Of those who drink (over 50% adults in US), about 29% report binge drinking on multiple occasions each month (i.e. chronic-binge drinkers), which results in about 1.5 billion episodes of binge drinking in the US each year. Fatty liver disease, one of the earliest and most common consequences of excessive heavy or binge drinking, can lead to more severe forms of liver injuries, including hepatitis, cirrhosis, and hepatocellular carcinoma. Our study will provide critical insights into the pathogenesis of alcohol-induced fatty liver disease. This study, if successful, may delineate key signaling pathways in alcoholic liver disease and identify new targets for preventing and treating alcoholic liver diseases as well as other forms of liver diseases. PUBLIC HEALTH RELEVANCE: Endoplasmic reticulum (ER) is a dynamic cellular structure that expands upon chronic alcohol drinking. This proposal tests a novel hypothesis that the activation of the IRE11-XBP1 pathway of the ER stress response upon alcohol consumption contributes significantly to the pathogenesis of alcoholic hepatic steatosis (faty liver) through direct regulation of the lipogenic program. This study, if successful, may establish a causal relationship between ER stress and alcoholic fatty liver, and provide one or more candidate targets for drug intervention in conditions exacerbated by excessive heavy or binge drinking.

描述（由申请人提供）：酗酒威胁着美国数百万美国人的健康。酒精性脂肪肝病或脂肪变性是过量饮酒最早和最常见的后果之一，可导致更严重的肝损伤，包括肝硬化、糖尿病、肝炎、纤维化和肝细胞癌。因此，了解酒精性脂肪肝的发病机制具有重要的临床和基础意义。最近的研究表明，内质网（ER）应激反应或未折叠蛋白反应（UPR）可能参与酒精性肝病的发病机制。这是一个非常有吸引力的模型，因为内质网是脂质生物合成、脂滴生物发生和酒精解毒的主要部位，并且据报道肝脏内质网在酗酒者中会扩张。然而，内质网应激与酒精性脂肪肝之间的因果关系尚未确定。我们和其他人最近表明 UPR 途径的 IRE11-XBP1 分支在脂质代谢中发挥着关键作用。令人兴奋的是，我们的初步数据显示，急性酒精挑战在几分钟内使肝脏中 IRE11 的活性翻倍，这表明内质网应激发生在饮酒后的早期阶段。此外，在两种患有更严重肝损伤的慢性酗酒小鼠模型中观察到了内质网应激。因此，该 R21 提案的目标是描述 IRE11-XBP1 分支在酒精性脂肪肝疾病发病机制中的作用。我们假设 UPR 的 IRE11-XBP1 分支直接调节肝脏中的脂肪生成程序，以响应长期酗酒，从而在酒精性脂肪肝疾病的发病机制中发挥关键作用。该假说将 IRE11-XBP1 分支和 ER 稳态确定为连接慢性酗酒和酒精性脂肪肝疾病的关键组成部分。使用最先进的方法（例如腺病毒 shRNA 来实现基因和肝脏特异性的时间敲低，基于 Phos 标签的方法来定量生理条件下的 ER 应激，以及组织 ChIP-qPCR 来定量转录因子与特定基因的结合肝脏中的启动子），我们将通过以下目的检验这一假设：（1）确定IRE11-XBP1通路的调节如何影响酒精性脂肪肝的发病机制； (2)探讨IRE11-XBP1通路响应酒精调节脂肪生成基因的基本机制。如果成功，据我们所知，这项研究将首次确定 UPR 与酒精性脂肪肝之间的因果关系。与人类健康的相关性：过量饮酒是全世界慢性肝病的主要原因。在饮酒者中（美国超过 50% 的成年人），约 29% 的人报告每月多次酗酒（即长期酗酒者），这导致美国每年约 15 亿次酗酒。脂肪肝病是过量饮酒或酗酒最早和最常见的后果之一，可导致更严重的肝损伤，包括肝炎、肝硬化和肝细胞癌。我们的研究将为酒精引起的脂肪肝的发病机制提供重要的见解。这项研究如果成功，可能会描绘出酒精性肝病的关键信号通路，并确定预防和治疗酒精性肝病以及其他形式肝病的新靶标。 公共卫生相关性：内质网 (ER) 是一种动态细胞结构，会随着长期饮酒而扩张。该提案测试了一个新的假设，即饮酒时 ER 应激反应的 IRE11-XBP1 通路的激活通过直接调节脂肪生成程序，对酒精性肝脂肪变性（脂肪肝）的发病机制做出了重大贡献。这项研究如果成功，可能会建立内质网应激与酒精性脂肪肝之间的因果关系，并为因过度酗酒或酗酒而加剧的病情提供一个或多个药物干预候选目标。