Zhou Bing, Luo Yunchen, Ji Nana, Mao Fei, Xiang Liping, Bian Hua, Zheng Ming-Hua, Hu Cheng, Li Yao, Lu Yan
Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education, Department of Endocrinology and Metabolism of Zhongshan Hospital, Fudan University, Shanghai, China.
Life Metab. 2022 Jun 10;1(2):161-174. doi: 10.1093/lifemeta/loac006. eCollection 2022 Oct.
Nonalcoholic steatohepatitis (NASH) has emerged as the major cause of end-stage liver diseases. However, an incomplete understanding of its molecular mechanisms severely dampens the development of pharmacotherapies. In the present study, through systematic screening of genome-wide mRNA expression from three mouse models of hepatic inflammation and fibrosis, we identified IGF2BP2, an N-methyladenosine modification reader, as a key regulator that promotes NASH progression in mice. Adenovirus or adeno-associated virus-mediated overexpression of IGF2BP2 could induce liver steatosis, inflammation, and fibrosis in mice, at least in part, by increasing Tab2 mRNA stability. Besides, hepatic overexpression of IGF2BP2 mimicked gene expression profiles and molecular pathways of human NASH livers. Of potential clinical significance, IGF2BP2 expression is significantly upregulated in the livers of NASH patients. Moreover, knockdown of IGF2BP2 substantially alleviated liver injury, inflammation, and fibrosis in diet-induced NASH mice. Taken together, our findings reveal an important role of IGF2BP2 in NASH, which may provide a new therapeutic target for the treatment of NASH.
非酒精性脂肪性肝炎（NASH）已成为终末期肝病的主要病因。然而，对其分子机制的不完全理解严重阻碍了药物治疗的发展。在本研究中，通过对三种肝脏炎症和纤维化小鼠模型的全基因组mRNA表达进行系统筛选，我们确定了一种N - 甲基腺苷修饰识别蛋白IGF2BP2，它是促进小鼠NASH进展的关键调节因子。腺病毒或腺相关病毒介导的IGF2BP2过表达至少部分通过增加Tab2 mRNA稳定性，可诱导小鼠肝脏脂肪变性、炎症和纤维化。此外，肝脏中IGF2BP2的过表达模拟了人类NASH肝脏的基因表达谱和分子途径。具有潜在临床意义的是，NASH患者肝脏中IGF2BP2的表达显著上调。此外，在饮食诱导的NASH小鼠中敲低IGF2BP2可显著减轻肝损伤、炎症和纤维化。综上所述，我们的研究结果揭示了IGF2BP2在NASH中的重要作用，这可能为NASH的治疗提供新的治疗靶点。
