The E3 ubiquitin-protein ligase Trim31 alleviates non-alcoholic fatty liver disease by targeting Rhbdf2 in mouse hepatocytes

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 () and Bochu Wang ()
Additional contact information
Minxuan Xu: Chongqing University of Education
Jun Tan: Chongqing University of Education
Wei Dong: Shandong First Medical University & Shandong Academy of Medical Sciences
Benkui Zou: Shandong First Medical University & Shandong Academy of Medical Sciences
Xuepeng Teng: Shandong First Medical University & Shandong Academy of Medical Sciences
Liancai Zhu: Chongqing University
Chenxu Ge: Chongqing University of Education
Xianling Dai: Chongqing University of Education
Qin Kuang: Chongqing University of Education
Shaoyu Zhong: Chongqing University of Education
Lili Lai: Chongqing University of Education
Chao Yi: Chongqing University of Education
Tingting Tang: Chongqing University of Education
Junjie Zhao: Chongqing University of Education
Longyan Wang: Chongqing University of Education
Jin Liu: Chongqing University of Education
Hao Wei: Chongqing University of Education
Yan Sun: Chongqing University of Education
Qiufeng Yang: Chongqing University of Education
Qiang Li: Chongqing University of Education
Deshuai Lou: Chongqing University of Education
Linfeng Hu: Chongqing University of Education
Xi Liu: Chongqing University of Education
Gang Kuang: Chongqing University of Education
Jing Luo: Chongqing University of Education
Mingxin Xiong: Chongqing University of Education
Jing Feng: Chongqing University of Education
Chufeng Zhang: Shandong First Medical University & Shandong Academy of Medical Sciences
Bochu Wang: Chongqing University

Nature Communications, 2022, vol. 13, issue 1, 1-20

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-28641-w

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