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

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  • Minxuan Xu

    (Chongqing University of Education
    Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University)

  • 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
    Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University)

  • 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
    Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University)

  • Qin Kuang

    (Chongqing University of Education
    Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University)

  • Qiang Li

    (Chongqing University of Education)

  • Deshuai Lou

    (Chongqing University of Education)

  • Linfeng Hu

    (Chongqing University of Education
    Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University)

  • 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)

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.

Suggested Citation

  • 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 & Qin, 2023. "Tripartite motif containing 26 prevents steatohepatitis progression by suppressing C/EBPδ signalling activation," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42040-9
    DOI: 10.1038/s41467-023-42040-9
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    References listed on IDEAS

    as
    1. 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 , 2022. "The E3 ubiquitin-protein ligase Trim31 alleviates non-alcoholic fatty liver disease by targeting Rhbdf2 in mouse hepatocytes," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    2. Bin Liu & Shangwen Jiang & Min Li & Xuelian Xiong & Mingrui Zhu & Duanzhuo Li & Lei Zhao & Lili Qian & Linhui Zhai & Jing Li & Han Lu & Shengnan Sun & Jiandie Lin & Yan Lu & Xiaoying Li & Minjia Tan, 2018. "Proteome-wide analysis of USP14 substrates revealed its role in hepatosteatosis via stabilization of FASN," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
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