Tripartite motif containing 26 prevents steatohepatitis progression by suppressing C/EBPδ signalling activation

Minxuan Xu (), Jun Tan (), Xin Liu, Li Han, Chenxu Ge, Yujie Zhang, Fufang Luo, Zhongqin Wang, Xiaoqin Xue, Liangyin Xiong, Xin Wang, Qinqin Zhang, Xiaoxin Wang, Qin Tian, Shuguang Zhang, Qingkun Meng, Xianling Dai, Qin Kuang, Qiang Li, Deshuai Lou, Linfeng Hu, Xi Liu, Gang Kuang, Jing Luo, Chunxiao Chang, Bochu Wang, Jie Chai, Shengbin Shi () and Lianyi Han ()
Additional contact information
Minxuan Xu: Chongqing University of Education
Jun Tan: Chongqing University of Education
Xin Liu: Shandong First Medical University & Shandong Academy of Medical Science
Li Han: Shandong First Medical University & Shandong Academy of Medical Science
Chenxu Ge: Chongqing University of Education
Yujie Zhang: Chongqing University of Education
Fufang Luo: Chongqing University of Education
Zhongqin Wang: Chongqing University of Education
Xiaoqin Xue: Chongqing University of Education
Liangyin Xiong: Chongqing University of Education
Xin Wang: Chongqing University of Education
Qinqin Zhang: Chongqing University of Education
Xiaoxin Wang: Chongqing University of Education
Qin Tian: Chongqing University of Education
Shuguang Zhang: Shandong First Medical University & Shandong Academy of Medical Science
Qingkun Meng: The Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine
Xianling Dai: Chongqing University of Education
Qin Kuang: 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
Chunxiao Chang: The Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine
Bochu Wang: Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University
Jie Chai: The Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine
Shengbin Shi: Nanjing Biomed Sciences Inc.
Lianyi Han: Fudan University

Nature Communications, 2023, vol. 14, issue 1, 1-22

Abstract: Abstract Currently potential preclinical drugs for the treatment of nonalcoholic steatohepatitis (NASH) and NASH-related pathopoiesis have failed to achieve expected therapeutic efficacy due to the complexity of the pathogenic mechanisms. Here we show Tripartite motif containing 26 (TRIM26) as a critical endogenous suppressor of CCAAT/enhancer binding protein delta (C/EBPδ), and we also confirm that TRIM26 is an C/EBPδ-interacting partner protein that catalyses the ubiquitination degradation of C/EBPδ in hepatocytes. Hepatocyte-specific loss of Trim26 disrupts liver metabolic homeostasis, followed by glucose metabolic disorder, lipid accumulation, increased hepatic inflammation, and fibrosis, and dramatically facilitates NASH-related phenotype progression. Inversely, transgenic Trim26 overexpression attenuates the NASH-associated phenotype in a rodent or rabbit model. We provide mechanistic evidence that, in response to metabolic insults, TRIM26 directly interacts with C/EBPδ and promotes its ubiquitin proteasome degradation. Taken together, our present findings identify TRIM26 as a key suppressor over the course of NASH development.

Date: 2023
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DOI: 10.1038/s41467-023-42040-9

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