炎症网络关键调节分子TMBIM1在非酒精性脂肪肝/脂肪肝炎中的功能和机制研究

Nonalcoholic fatty liver disease (NAFLD) is the highest incidence of chronic liver disease in China, of which 10 to 20% will be further development of nonalcoholic steatohepatitis (NASH), and had a higher risk of developing cirrhosis and hepatocellular carcinoma. Currently, there is no effective clinical drug for the treatment of NASH. TMBIM1 is a 7 transmembrane protein localized on the lysosomal membrane. Previous studies have shown that TMBIM1 can modulate apoptosis、calcium homeostasis and vascular remodeling, and there is no study related its function in liver diseases. Our previous screening revealed that TMBIM1 mRNA and protein levels were significantly lower in the liver of NAFLD/NASH patients and high-fat diet fed mice. Subsequently, using hepatocyte specific TMBIM1 knockout mice, we demonstrated that TMBIM1 deficiency significantly promoted insulin resistance and liver lipid deposition upon a high-fat diet. More importantly, using microarray and bioinformatic analysis, we first identified and confirmed that TMBIM1 is novel key regulator of inflammation network, TMBIM1 deficiency can significantly promote the activation of TLR4 signaling pathway and downstream cytokines. However, how TMBIM1 regulates TLR4 signaling pathways and NAFLD/NASH is unclear. Based on the previous study, we plane to elucidate the mechanism by which TMBIM1 regulates TLR4 signal pathway and NAFLD/NASH process, and to evaluate whether TMBIM1 can be served as a therapeutic target for NAFLD/NASH. Furthermore, we will elucidate its role in the occurrence and development of HCC induced by high-fat and high carbohydrate diet.

非酒精性脂肪肝病（NAFLD）是发病率很高的慢性肝病，其中10～20%会进一步发展为非酒精性脂肪肝炎（NASH），并有较高风险进展为肝硬化和肝癌。目前尚无有效干预治疗NASH的临床药物。多泡体调控蛋白TMBIM1是一个7次跨膜蛋白，我们前期应用肝脏细胞特异性基因敲除小鼠发现该基因缺失表达能显著促进高脂饮食引起的胰岛素抵抗和肝脏脂质沉积，并首次发现其可通过调节MVB过程促进Tlr4的溶酶体降解，抑制TLR4信号通路，相关研究2017年发表于国际顶级期刊Nature Medicine 。本项目拟在前期研究基础上通过系列实验，结合高脂高碳水化合物饮食诱发肝癌模型系统构建TMBIM1调节TLR4相关上下游通路参与NAFLD/NASH/肝硬化/肝癌疾病不同进程的信号通路网络，明确其在炎癌进展中的分子机制，并探讨TMBIM1作为分子靶点逆转干预NAFLD/NASH向肝纤维化、肝癌进展的可行性。

非酒精性脂肪肝病（NAFLD）是指除酒精和其他明确损肝因素所致的以肝细胞内脂肪过度沉积为主要特征的临床病理综合征。本项目受国家自然基金资助（重大研究计划），依托中国人民解放军第二军医大学，并与武汉大学共同合作，历时1年，对一个炎症网络关键调节分子TMBIM1在非酒精性脂肪肝/脂肪肝炎中的功能和机制进行了研究。本研究表明TMBIM肝细胞特异性敲除显著促进了高脂饮食诱导小鼠胰岛素抵抗、肝脂质沉积和炎症反应，且通过分子生物学手段发现TMBIM1是通过Nedd4l使其发生泛素化，促进MVB的形成从而促进了Tlr4的降解来抑制NAFLD/NASH的发生发展。进一步的研究表明，外源性导入TMBIM1后，明显改善了小鼠和食蟹猴高脂饮食诱导的代谢综合征和肝脂变性。本项目首次发现并证实了TMBIM1是一个非常重要的炎症网络调节分子，并联合生物信息和分子生物学手段揭示了TMBIM1调控NAFLD/NASH的分子机制，而且在小鼠和食蟹猴上探究了TMBIM1对NAFLD/NASH的治疗效果，为NAFLD/NASH的发生发展机制提供了新的线索并提供了新的治疗靶点。