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: 10294073
• 负责人: Lin Jia
• 金额: $ 14.95万
• 依托单位: UNIVERSITY OF TEXAS DALLAS
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10294073
• 关键词: Role; Hepatocyte; TLR4; Alcohol; induced

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 过量饮酒引起的慢性肝病已被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 酒精性肝病（ALD）的发展。特别是，由以下物质产生的强烈炎症反应： 肠源性脂多糖 (LPS) 与其细胞表面受体 Toll 样受体 4 之间的相互作用 (TLR4)，极大地促进酒精引起的肝损伤。然而，确切的 TLR4 表达细胞类型 介导这种效应很大程度上是未知的。最近，我们和其他人报道了肝细胞 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 初步数据显示，缺乏肝细胞TLR4的小鼠可以减轻酒精引起的早期肝损伤 并减少白色脂肪组织的炎症。相比之下，肝细胞中TLR4重新激活的小鼠 长期饮酒后，肝脏中会积累更多的甘油三酯含量。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 利用我们的两种独特的小鼠模型，可以选择性地消除和重新激活 TLR4 表达 肝细胞分别追求以下特定目标。在具体目标1中，我们将确定以下角色： 肝细胞 TLR4 在酒精性脂肪性肝炎发展中的作用。我们将使用缺乏 TLR4 的小鼠 特异地在肝细胞中表达，以检验肝细胞 TLR4 是 长期饮酒引起急性酒精性脂肪性肝炎。在具体目标 2 中，我们 将为小鼠长期喂食含乙醇的液体饮食长达 8 周。我们将检验以下假设： 酒精诱导的胰岛素抵抗的发生需要肝细胞 TLR4。在具体目标 3 中，我们 将使用 TLR4 可重新激活的小鼠模型，该模型可以恢复内源性 TLR4 表达，特别是在 肝细胞以确定酒精相关性脂肪性肝炎和胰岛素中肝细胞 TLR4 的充足性 反抗。这些研究将极大地增强我们对肝细胞TLR4在肝细胞中的调节作用的认识。 酒精性肝损伤和相关代谢紊乱，并促进新的抗 ALD 药物的开发 疗法。