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

摘要 过量饮酒导致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，由病毒引起的强烈炎症反应 肠源性内毒素与其细胞表面受体Toll样受体4的相互作用 (TLR4)，极大地促进了酒精性肝损伤。然而，表达TLR4的确切细胞类型 这种调节作用在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诱导的早期肝损伤 并减少白色脂肪组织中的炎症。相反，TLR4在肝细胞中重新激活的小鼠 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在酒精性脂肪性肝炎和胰岛素抵抗中的潜在作用我们会 利用我们的两个独特的小鼠模型，可以选择性地消融和重新激活TLR4在 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 肝细胞TLR4在酒精性脂肪性肝炎发病中的作用我们将使用缺乏TLR4的小鼠 特异性地在肝细胞中表达，以检验肝细胞TLR4是肝细胞所需的假设 急、慢性饮酒所致酒精性脂肪性肝炎的研究进展。在具体目标2中，我们 将长期喂给小鼠含乙醇的液体饮食长达8周。我们将检验这一假设 肝细胞TLR4在酒精性胰岛素抵抗的发生发展中起重要作用。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的表达 肝细胞测定酒精性脂肪性肝炎和胰岛素中肝细胞TLR4的充分性 抵抗。这些研究将极大地提高我们对肝细胞TLR4调控作用的认识 酒精性肝损伤及相关代谢紊乱和促进新抗酒精性肝病的发展 治疗。

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.