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

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.

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。

众所周知:分泌型TNF-a（sTNF-a）是连接肥胖和胰岛素抵抗的枢纽分子，我们结果表明单纯阻断sTNF-a的生物学效应不能逆转高糖高脂饮食诱导wistar大鼠的肝源性胰岛素抵抗， 免疫组化显示肝脏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。同时体外实验证实跨膜型TNF-a（TM-TNF-a）和分泌型TNF-a在胰岛素抵抗中发挥不同的作用：TM-TNF-a 增强胰岛素的敏感性而sTNF-a则抑制胰岛素的敏感性。 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。我们体内、体外实验证实HMGB1既可以诱导胰岛素抵抗又能参与细胞的氧化应激和脂质过氧化反应，针对HMGB1的中和性抗体可以有效抑制这两次打击的发生发展；HMGB1抗体治疗高脂饮食诱导C57BL/6和ob/ob小鼠发生NASH的基因芯片结果提供了HMGB1 可能作用的分子机制与信号通路，为治疗肥胖诱导的NASH提供了更多地潜在的新分子靶点。