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Systemic metabolic syndrome significantly increases the risk of morbidity and mortality in patients with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). However, no effective therapeutic strategies are available, practically because our understanding of its complicated pathogenesis is poor. Here we identify the tripartite motif-containing protein 31 (Trim31) as an endogenous inhibitor of rhomboid 5 homolog 2 (Rhbdf2), and we further determine that Trim31 directly binds to Rhbdf2 and facilitates its proteasomal degradation. Hepatocyte-specific Trim31 ablation facilitates NAFLD-associated phenotypes in mice. Inversely, transgenic or ex vivo gene therapy-mediated Trim31 gain-of-function in mice with NAFLD phenotypes virtually alleviates severe deterioration and progression of steatohepatitis. The current findings suggest that Trim31 is an endogenous inhibitor of Rhbdf2 and downstream cascades in the pathogenic process of steatohepatitis and that it may serve as a feasible therapeutical target for the treatment of NAFLD/NASH and associated metabolic disorders. © 2022. The Author(s).


Minxuan Xu, Jun Tan, Wei Dong, Benkui Zou, Xuepeng Teng, Liancai Zhu, Chenxu Ge, Xianling Dai, Qin Kuang, Shaoyu Zhong, Lili Lai, Chao Yi, Tingting Tang, Junjie Zhao, Longyan Wang, Jin Liu, Hao Wei, Yan Sun, Qiufeng Yang, Qiang Li, Deshuai Lou, Linfeng Hu, Xi Liu, Gang Kuang, Jing Luo, Mingxin Xiong, Jing Feng, Chufeng Zhang, Bochu Wang. The E3 ubiquitin-protein ligase Trim31 alleviates non-alcoholic fatty liver disease by targeting Rhbdf2 in mouse hepatocytes. Nature communications. 2022 Feb 25;13(1):1052

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PMID: 35217669

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