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Nat Med:武汉大学李红良研究组发表非酒精性脂肪肝致病机理研究论文

摘要 : 2017年5月8日,国际学术权威刊物自然出版集团旗下子刊《Nature Medicine》杂志在线发表了武汉大学基础医学院院长李红良教授团队最新研究成果。

 2017年5月8日,国际学术权威刊物自然出版集团旗下子刊《Nature Medicine》杂志在线发表了武汉大学基础医学院院长李红良教授团队最新研究成果。研究首次揭示了多泡体(MVB)调控蛋白Tmbim1在非酒精性脂肪肝病(NAFLD)和非酒精性脂肪肝炎(NASH)中的关键负调控作用,并深入阐明其分子机制。

NAFLD是中国发病率最高的慢性肝病类型,目前国内有超过1.5亿患者,其中10%~20%会进一步发展为NASH,表现为严重的炎症反应及肝细胞损伤,常常伴有纤维化。NASH病程进展迅速,并有较高风险发展为肝硬化和肝细胞癌等严重肝脏疾病。目前,在世界范围内尚无有效治疗NASH的临床药物且其发病机制尚不明确。

研究团队长期致力于对心血管和肝脏代谢性疾病的研究。前期研究表明,溶酶体介导的蛋白降解紊乱是NASH进程的重要环节,并且已成为多种疾病的药物开发靶点。然而,溶酶体介导的蛋白降解是否可以作为NASH的治疗靶点目前尚无报道。

该项目自2008年开始,经过近9年的探索,运用多种基因工程动物疾病模型和分子生物学手段,终于证实Tmbim1对肝脏脂质堆积、胰岛素抵抗、慢性炎症和纤维化等NASH病理过程发挥关键的抑制作用。进一步分子机制研究阐明,Tmbim1是MVB-溶酶体通路的一个新的调控分子,通过促进Tlr4的溶酶体降解,显著改善并逆转NASH进程。

该研究是肝脏代谢性疾病研究领域的又一重要发现,表明通过靶向MVB调节因子从而调控溶酶体介导的蛋白降解紊乱是治疗NASH的有效手段。该研究还为深入理解NASH的发病机制提出了新的认识,为临床防治NASH及相关疾病提供了新靶点和新策略。

原文链接:

Tmbim1 is a multivesicular body regulator that protects against non-alcoholic fatty liver disease in mice and monkeys by targeting the lysosomal degradation of Tlr4

原文摘要:

Non-alcoholic steatohepatitis (NASH) is an increasingly prevalent liver pathology that can progress from non-alcoholic fatty liver disease (NAFLD), and it is a leading cause of cirrhosis and hepatocellular carcinoma. There is currently no pharmacological therapy for NASH. Defective lysosome-mediated protein degradation is a key process that underlies steatohepatitis and a well-recognized drug target in a variety of diseases; however, whether it can serve as a therapeutic target for NAFLD and NASH remains unknown. Here we report that transmembrane BAX inhibitor motif-containing 1 (TMBIM1) is an effective suppressor of steatohepatitis and a previously unknown regulator of the multivesicular body (MVB)-lysosomal pathway. Tmbim1 expression in hepatocytes substantially inhibited high-fat diet–induced insulin resistance, hepatic steatosis and inflammation in mice. Mechanistically, Tmbim1 promoted the lysosomal degradation of toll-like receptor 4 by cooperating with the ESCRT endosomal sorting complex to facilitate MVB formation, and the ubiquitination of Tmbim1 by the E3 ubiquitin ligase Nedd4l was required for this process. We also found that overexpression of Tmbim1 in the liver effectively inhibited a severe form of NAFLD in mice and NASH progression in monkeys. Taken together, these findings could lead to the development of promising strategies to treat NASH by targeting MVB regulators to properly orchestrate the lysosome-mediated protein degradation of key mediators of the disease.

来源: Nature Medicine 浏览次数:0

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