Nature Communications (Oct 2023)
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,
- Lianyi Han
Affiliations
- Minxuan Xu
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education
- Jun Tan
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education
- Xin Liu
- Department of Gastrointestinal Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical Science
- Li Han
- Department of Gastrointestinal Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical Science
- Chenxu Ge
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education
- Yujie Zhang
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education
- Fufang Luo
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education
- Zhongqin Wang
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education
- Xiaoqin Xue
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education
- Liangyin Xiong
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education
- Xin Wang
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education
- Qinqin Zhang
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education
- Xiaoxin Wang
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education
- Qin Tian
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education
- Shuguang Zhang
- Department of Gastrointestinal Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical Science
- Qingkun Meng
- Geriatrics Department, The Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine
- Xianling Dai
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education
- Qin Kuang
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education
- Qiang Li
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education
- Deshuai Lou
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education
- Linfeng Hu
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education
- Xi Liu
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education
- Gang Kuang
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education
- Jing Luo
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education
- Chunxiao Chang
- Geriatrics Department, 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
- Geriatrics Department, The Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine
- Shengbin Shi
- New Drug Technology R&D Center, Nanjing Biomed Sciences Inc.
- Lianyi Han
- Greater Bay Area Institute of Precision Medicine (Guangzhou), School of Life Sciences, Fudan University
- DOI
- https://doi.org/10.1038/s41467-023-42040-9
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 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.
