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.

抽象的 过度饮酒引起的慢性肝病已被认为是严重的健康问题 在美国。越来越多的证据表明，炎症在 酒精性肝病（ALD）的发展。特别是，由 肠道来源的脂多糖（LPS）及其细胞表面受体Toll样受体4之间的相互作用4 （TLR4），极大地导致酒精诱导的肝损伤。但是，确切的表达TLR4的细胞类型 介导这种效果在很大程度上未知。最近，我们和其他人报告说肝细胞TLR4调节 肥胖相关的慢性炎症，胰岛素抵抗和非酒精性肝病。此外，我们的 初步数据表明，缺乏肝细胞TLR4的小鼠减弱了酒精引起的早期肝损伤 并减少白色脂肪组织的炎症。相反，肝细胞中具有TLR4重新激活的小鼠 慢性饮酒后，在肝脏中积累了更多的甘油三酸酯含量。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 利用我们的两个独特的鼠标模型，可以选择性地烧蚀并重新激活TLR4的表达 肝细胞分别追求以下特定目标。在特定目标1中，我们将确定 肝细胞TLR4在酒精脂肪性肝炎的发展中。我们将使用缺少TLR4的老鼠 在肝细胞中特别表达以检验肝细胞TLR4需要的假设 由急性智力乙醇饮用引起的酒精性脂肪性肝炎的发展。在特定的目标2中，我们 将长达8周的长期喂养小鼠含有乙醇的液体饮食。我们将检验以下假设 肝细胞TLR4是饮酒引起的胰岛素抵抗所必需的。在特定的目标3中，我们 将使用TLR4可反应的小鼠模型，该模型可以恢复内源性TLR4表达 肝细胞确定与酒精相关的脂肪性肝炎和胰岛素中肝细胞TLR4的充分性 反抗。这些研究将大大增强我们对肝细胞TLR4在调节作用中的了解 酒精性肝损害和相关的代谢疾病，并促进新的抗ald的发展 疗法。