Role of Hepatocyte TLR4 in Alcohol-induced Steatohepatitis and Insulin Resistance

肝细胞TLR4在酒精性脂肪性肝炎和胰岛素抵抗中的作用

• 批准号: 9243504
• 负责人: Lin Jia
• 金额: $ 14.95万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9243504
• 关键词: Acute; Adipose tissue; Alcohol consumption; Alcoholic Hepatitis; Alcoholic Liver Diseases; Alcoholic beverage heavy drinker; Alcoholic liver damage; Alcohols; Attenuated; Blood Circulation; Cell Communication; Cell Surface Receptors; Cells; Cessation of life; Chronic; Cirrhosis; Data; Development; Diet; Disease; Ethanol; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Genes; Health; Heavy Drinking; Hepatic; Hepatitis; Hepatocyte; Impairment; Inflammation; Inflammatory; Inflammatory Response; Insulin; Insulin Resistance; Knowledge; Life; Lipopolysaccharides; Liquid substance; Liver; Liver diseases; Mediating; Metabolic Diseases; Modeling; Mus; National Institute on Alcohol Abuse and Alcoholism; Obesity; Pathway interactions; Physiological; Play; Regimen; Reporting; Role; Signal Transduction; Steatohepatitis; TLR4 gene; Testing; Tissues; Triglycerides; United States; cell type; chronic alcohol ingestion; chronic liver disease; disability; effective therapy; experimental study; feeding; glucose tolerance; glucose uptake; improved; inflammatory marker; insulin sensitivity; liver inflammation; liver injury; mortality; mouse model; non-alcoholic; novel therapeutics; problem drinker; restoration; skills; treatment strategy

Abstract Excessive alcohol drinking-induced chronic liver disease has been recognized as a serious health problem in the United States. Increasing evidence suggests that inflammation plays an essential role in the development of alcoholic liver disease (ALD). In particular, the potent inflammatory response produced by the interactions between gut-derived lipopolysaccharide (LPS) and its cell surface receptor, Toll-like receptor 4 (TLR4), greatly contribute to alcohol-induced liver injury. However, the exact TLR4-expressing cell type that mediates this effect is largely unknown. Recently, we and others reported that hepatocyte TLR4 regulates obesity-related chronic inflammation, insulin resistance, and nonalcoholic liver disease. Furthermore, our preliminary data showed that mice lacking hepatocyte TLR4 had attenuated alcohol-induced early liver injury and reduced inflammation in white adipose tissue. In contrast, mice with TLR4 reactivation in hepatocyte accumulated more triglyceride content in the liver after chronic alcohol drinking. These findings support the potential role of hepatocyte TLR4 in mediating alcohol-induced steatohepatitis and insulin resistance. We will take advantage of our two unique mouse models that can selectively ablate and reactivate TLR4 expression in hepatocytes, respectively, to pursue the following specific aims. In specific aim 1, we will determine the role of hepatocyte TLR4 in the development of alcoholic steatohepatitis. We will use the mice lacking TLR4 expression specifically in hepatocyte to test the hypothesis that hepatocyte TLR4 is required for the development of alcoholic steatohepatitis induced by acute-on-chronic ethanol drinking. In specific aim 2, we will feed mice an ethanol-containing liquid diet chronically up to 8 weeks. We will test the hypothesis that hepatocyte TLR4 is required for the development of alcohol-induced insulin resistance. In specific aim 3, we will use a TLR4 reactivatable mouse model that can restore endogenous TLR4 expression specifically in hepatocytes to determine the sufficiency of hepatocyte TLR4 in alcohol-related steatohepatitis and insulin resistance. These studies will greatly enhance our knowledge of the regulatory role of hepatocyte TLR4 in alcoholic liver damage and associated metabolic disorders and facilitate the development of new anti-ALD therapies.

摘要 过量饮酒引起的慢性肝病已被公认为是一个严重的健康问题 在美国越来越多的证据表明，炎症在炎症反应中起着重要作用。 酒精性肝病（ALD）的发展。特别是，由炎症因子产生的强有力的炎症反应 肠源性脂多糖（LPS）与其细胞表面受体Toll样受体4的相互作用 TLR4在酒精性肝损伤中的作用然而，表达TLR4的确切细胞类型， 介导这种效应的机制在很大程度上是未知的。最近，我们和其他人报道肝细胞TLR4调节 肥胖相关的慢性炎症、胰岛素抵抗和非酒精性肝病。而且我们的 初步数据显示，缺乏肝细胞TLR4的小鼠减轻了酒精诱导的早期肝损伤， 并减少白色脂肪组织中的炎症。相反，在肝细胞中TLR4再活化的小鼠， 在长期饮酒后，肝脏中积累了更多的甘油三酯。这些发现支持 肝细胞TLR4在介导酒精诱导的脂肪性肝炎和胰岛素抵抗中的潜在作用。我们将 利用我们的两种独特的小鼠模型，可以选择性地消融和重新激活TLR4表达， 肝细胞，分别追求以下具体目标。在具体目标1中，我们将确定 肝细胞TLR4在酒精性脂肪性肝炎发生中的作用我们将使用缺乏TLR4的小鼠， 在肝细胞中特异性表达，以检验肝细胞TLR4是肝细胞TLR4表达所必需的假设。 慢性饮酒诱发急性酒精性脂肪性肝炎的发生。在具体目标2中，我们 将给小鼠长期喂食含乙醇的流质食物长达8周。我们将检验这个假设， 肝细胞TLR4是酒精诱导的胰岛素抵抗的发展所必需的。在具体目标3中，我们 将使用TLR4可再活化的小鼠模型，该模型可以特异性地恢复内源性TLR4表达， 肝细胞，以确定肝细胞TLR4在酒精相关脂肪性肝炎和胰岛素 阻力这些研究将大大提高我们对肝细胞TLR4在肝细胞凋亡中的调节作用的认识。 酒精性肝损伤和相关的代谢紊乱，并促进新的抗ALD的发展 治疗