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

  • Nat Commun. 2023 Oct 11;14(1):6384. doi: 10.1038/s41467-023-42040-9.
Minxuan Xu  #  1  2 ,  Jun Tan  #  3 ,  Xin Liu  #  4 ,  Li Han  #  4 ,  Chenxu Ge  #  5  6 ,  Yujie Zhang  5 ,  Fufang Luo  5 ,  Zhongqin Wang  5 ,  Xiaoqin Xue  5 ,  Liangyin Xiong  5 ,  Xin Wang  5 ,  Qinqin Zhang  5 ,  Xiaoxin Wang  5 ,  Qin Tian  5 ,  Shuguang Zhang  4 ,  Qingkun Meng  7 ,  Xianling Dai  5  6 ,  Qin Kuang  5  6 ,  Qiang Li  5 ,  Deshuai Lou  5 ,  Linfeng Hu  5  6 ,  Xi Liu  5 ,  Gang Kuang  5 ,  Jing Luo  5 ,  Chunxiao Chang  7 ,  Bochu Wang  6 ,  Jie Chai  7 ,  Shengbin Shi  8 ,  Lianyi Han  9
Affiliations
  • 1. Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education, 400067, Chongqing, P. R. China. [email protected].
  • 2. Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University, 400030, Chongqing, P. R. China. [email protected].
  • 3. Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education, 400067, Chongqing, P. R. China. [email protected].
  • 4. Department of Gastrointestinal Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical Science, 250117, Jinan, P. R. China.
  • 5. Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education, 400067, Chongqing, P. R. China.
  • 6. Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University, 400030, Chongqing, P. R. China.
  • 7. Geriatrics Department, The Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, 250117, Jinan, P. R. China.
  • 8. New Drug Technology R&D Center, Nanjing Biomed Sciences Inc., 210003, Nanjing, P. R. China. [email protected].
  • 9. Greater Bay Area Institute of Precision Medicine (Guangzhou), School of Life Sciences, Fudan University, 315211, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 37821436 DOI: 10.1038/s41467-023-42040-9
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.

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