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）：酒精中毒威胁着美国数百万美国人的健康。酒精脂肪肝病或脂肪变性是过量饮酒的最早，最常见的后果之一，可能导致更严重的肝脏损伤形式，包括肝硬化，糖尿病，肝炎，纤维化，纤维化和肝细胞癌。因此，了解酒精引起的脂肪肝病的发病机理具有很大的临床和基本重要性。最近的研究表明，内质网（ER）对应激的反应可能参与酒精性肝病的发病机理。这是一个非常有吸引力的模型，因为ER是脂质生物合成，脂质液滴生物发生和酒精排毒的主要位点，并且据报道肝ER在酒精中毒中扩展。但是，尚未建立ER应激与酒精脂肪肝之间的因果关系。我们和其他人最近表明，UPR途径的IRE11-XBP1分支在脂质代谢中起着至关重要的作用。令人兴奋的是，我们的初步数据表明，急性酒精挑战在几分钟内肝脏在肝脏中的活性增加了一倍，这表明ER应力发生在饮酒后的早期阶段。此外，在两个慢性饮用小鼠模型中观察到ER应力，具有更严重的肝损伤。因此，该R21提案的目的是描述IRE11-XBP1分支在酒精脂肪肝病发病机理中的作用。我们假设UPR的IRE11-XBP1分支直接调节肝脏中的脂肪生成程序，以响应慢性饮酒，从而在酒精脂肪肝病的发病机理中起关键作用。该假设将IRE11-XBP1分支和ER同义分支确定为连接慢性饮酒和酒精脂肪肝病的关键组成部分。使用艺术方法（例如，腺病毒shRNA实现基因和肝特异性时间敲低，基于PHOS-TAG的基于PHOS-TAG的方法，以在生理条件和组织CHIP-QPCR下量化ER应激，以量化转录因子与肝脏中特定基因启动子的结合，我们将在肝脏中与以下途径进行测试。酒精脂肪肝的发病机理； （2）探索IRE11-XBP1途径响应于酒精的脂肪生成基因的基本机制。如果成功的话，这项研究将首次确定UPR与酒精脂肪肝病之间的因果关系。与人类健康的相关性：过度的酒精摄入是全球慢性肝病的主要原因。在喝酒的人中（我们在美国中有50％以上），大约有29％的人每月多次报告暴饮暴食（即慢性饮酒者），每年在美国每年大约有15亿次暴饮暴食。脂肪肝疾病是过度重或暴饮暴食的最早，最常见的后果之一，可能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病的发病机理提供关键的见解。这项研究，如果成功的话，可以描述酒精性肝病中的关键信号通路，并确定预防和治疗酒精性肝病以及其他形式的肝脏疾病的新靶标。 公共卫生相关性：内质网（ER）是一种动态的细胞结构，可在慢性饮酒时扩展。该提案检验了一个新的假设，即饮酒中ER应激反应的IRE11-XBP1途径的激活通过直接调节脂肪生成计划对酒精性肝脂肪变性（FATY肝脏）的发病机理显着促进。这项研究，如果成功的话，可以在ER应力和酒精脂肪肝之间建立因果关系，并在过量或暴饮暴食的情况下为药物干预提供一个或多个候选靶标。