HMGB1在肥胖诱导的非酒精性脂肪性肝炎中的作用及其分子机制研究

项目名称： HMGB1在肥胖诱导的非酒精性脂肪性肝炎中的作用及其分子机制研究

项目编号： No.81202300

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学免疫学、法医学

项目作者： 梁慧芳

作者单位： 华中科技大学

项目金额： 23万元

中文摘要： TNF-a在肥胖诱导的胰岛素抵抗中发挥重要作用，但前期结果表明单纯阻断TNF-a的生物学效应不能逆转肥胖诱导的肝脏胰岛素抵抗，而是进一步发展为非酒精性脂肪性肝炎，在此过程中发现肝脏组织HMGB1胞外水平明显升高，运用HMGB1中和抗体明显阻止NASH的进展，提示HMGB1可能在肥胖诱导的NASH的发生发展中起作用。NASH发病机制的二次打击学说认为肥胖诱导的慢性炎症是第一次打击，氧化应激和脂质过氧化造成肝细胞损伤则是第二次打击。HMGB1既是一种炎症介质又能参与细胞的氧化应激和脂质过氧化反应，故我们假设HMGB1通过二次打击，促进NASH的发生发展。本项目拟从体内、体外两个水平探讨HMGB1在肥胖诱导的NASH中的作用，并进一步探讨其可能的分子机制，为治疗肥胖诱导的NASH提供新的分子靶点。

中文关键词： 肥胖；非酒精性脂肪性肝炎；胰岛素抵抗；高迁移率族蛋白B1；肿瘤坏死因子alpha

英文摘要： TNF-a plays an important role in insulin resistance induced by obesity, but our results suggested that blocking the biological effect of TNF-a can not reverse hepatic insulin resistance and further development of nonalcoholic steatohepatitis (NASH). When NASH developed, we found that the levels of HMGB1 were significantly elevated in liver and the progression of NASH could be compromised by antibody of HMGB1. These results suggested that HMGB1 may play a role in NASH. The two-hit theory of NASH pathogenesis hold the opinion that liver chronic inflammation induced by obesity is the first blow, while oxidative stress and lipid peroxidation resulted in liver cell injury is the second blow to promote the development of NASH. So we hypothesized that HMGB1 through these two blows to accelerate the progression of NASH. This project will investigate the role and possible molecular mechanisms of HMGB1 in the development of NASH induced by obesity and provide a new molecular target for the treatment of NASH induced by obesity.

英文关键词： Obesity；Nonalcoholic steatohepatitis；Insulin resistance；High mobility group box protein B1；Tumor necrosis factor alpha