2. Academic Validation
  3. Tripartite motif containing 26 prevents steatohepatitis progression by suppressing C/EBPδ signalling activation

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

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. minxuanxu@foxmail.com.
  • 2 Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University, 400030, Chongqing, P. R. China. minxuanxu@foxmail.com.
  • 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. tanjun@cque.edu.cn.
  • 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. shisb_njbms@yeah.net.
  • 9 Greater Bay Area Institute of Precision Medicine (Guangzhou), School of Life Sciences, Fudan University, 315211, Shanghai, China. hanlianyi@fudan.edu.cn.
  • # 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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