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  • ECM1 attenuates hepatic fibrosis by interfering with mediators of latent TGF-β1 activation

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Hepatology
Original research
ECM1 attenuates hepatic fibrosis by interfering with mediators of latent TGF-β1 activation
  1. Frederik Link1,
  2. Yujia Li1,
  3. Jieling Zhao2,3,
  4. Stefan Munker4,5,
  5. Weiguo Fan6,
  6. Zeribe C Nwosu1,7,
  7. Ye Yao1,
  8. Shanshan Wang8,
  9. Chenjun Huang1,9,
  10. Roman Liebe10,
  11. Seddik Hammad1,
  12. Hui Liu11,
  13. Chen Shao11,
  14. Chunfang Gao9,
  15. Bing Sun12,
  16. Natalie J Török13,
  17. Huiguo Ding14,
  18. Matthias PA Ebert1,15,16,
  19. Honglei Weng1,
  20. Peter ten Dijke17,
  21. Dirk Drasdo2,3,
  22. Steven Dooley1,
  23. Sai Wang1
  1. 1Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
  2. 2INRIA de Saclay, Palaiseau, France
  3. 3IfADo, Dortmund, Germany
  4. 4Department of Medicine II, University Hospital, LMU, Munich, Germany
  5. 5Liver Center Munich, University Hospital, LMU, Munich, Germany
  6. 6Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, People's Republic of China
  7. 7Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA
  8. 8Beijing Institute of Hepatology, Beijing You’an Hospital, Capital Medical University, Beijing, People's Republic of China
  9. 9Department of Clinical Laboratory Medicine Center, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of China
  10. 10Clinic of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke-University, Magdeburg, Germany
  11. 11Department of Pathology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, People's Republic of China
  12. 12State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, People's Republic of China
  13. 13Gastroenterology and Hepatology, Stanford University, Palo Alto, CA, USA
  14. 14Department of Gastroenterology and Hepatology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, People's Republic of China
  15. 15Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, Heidelberg, Germany
  16. 16DKFZ-Hector Cancer Institute at the University Medical Center, Mannheim, Germany
  17. 17Oncode Institute and Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands
  1. Correspondence to Dr Sai Wang, Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; sai.wang{at}medma.uni-heidelberg.de; Prof. Steven Dooley, Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; steven.dooley{at}medma.uni-heidelberg.de

Abstract

Objective Extracellular matrix protein 1 (ECM1) serves as a gatekeeper of hepatic fibrosis by maintaining transforming growth factor-β1 (TGF-β1) in its latent form. ECM1 knockout (KO) causes latent (L) TGF-β1 activation, resulting in hepatic fibrosis with rapid mortality. In chronic liver disease (CLD), ECM1 decreases with increasing CLD severity. We investigate the regulatory role of ECM1 in TGF-β1 bioavailability and its impact on CLD progression.

Design RNAseq was performed to analyse hepatic gene expression. Functional assays were performed using hepatic stellate cells (HSCs), Ecm1-KO and Fxr-KO mice, patient liver tissue and computer simulations.

Results Expression of LTGF-β1 activators, including thrombospondins (TSPs), ADAMTS proteases and matrix metalloproteinases (MMPs), increased along with profibrotic gene expression in liver tissue of Ecm1-KO mice. In HSCs, overexpression of ECM1 prevented LTGF-β1 activation mediated by TSP-1, ADAMTS1, and MMP-2/9. In vitro interaction assays demonstrated that ECM1 inhibited LTGF-β1 activation by interacting with TSP-1 and ADAMTS1 via their respective, intrinsic KRFK or KTFR amino acid sequences and by suppressing MMP-2/9 proteolytic activity. In mice, ECM1 overexpression attenuated KRFK-induced LTGF-β1 activation while KTFR treatment reversed Ecm1-KO-mediated and Fxr-KO-mediated liver injury. In patients with CLD, ECM1 expression was inversely correlated with TSP-1, ADAMTS1, MMP-2/9 expression and LTGF-β1 activation. And, these results were complemented by a computational compartment model representing the key network of cellular phenotypes and predicted interactions in liver fibrogenesis.

Conclusion Our findings underscore the hepatoprotective effect of ECM1, which interferes with mediators of LTGF-β1 activation, suggesting ECM1 or its representative peptide as potential antifibrotic therapies in CLD.

  • CHRONIC LIVER DISEASE
  • HEPATIC STELLATE CELL
  • EXTRACELLULAR MATRIX
  • TGF-BETA
  • HEPATIC FIBROSIS

Data availability statement

Data are available in a public, open access repository. Data are available on reasonable request.

https://doi.org/10.1136/gutjnl-2024-333213

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    Data availability statement

    Data are available in a public, open access repository. Data are available on reasonable request.

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    Footnotes

    • X @LiebeRoman

    • SD and SW contributed equally.

    • Contributors Conceptualisation: SD and SW. Methodology: FL, SW, YL, JZ, DD, SM, WF, ZCN, YY, CH and SH. Investigation: FL, SW, YL, JZ, SM, ZCN, WF, SSW, YY, HL, CS and DD. Visualisation: FL, SW, JZ, DD, YY and CH. Funding acquisition: SD. Project administration: SD, SW and FL. Supervision: SW and SD. Writing–original: FL, SW and SD. Writing–review: FL, SW, SD, JZ, DD, PTD, ZCN, RL, HW, ME, NJT, BS, HD, CG, SSW and SD acted as guarantors. AlphaFold3 was used for predicting the interaction between two proteins.

    • Funding This work was supported by the Deutsche Forschungsgemeinschaft (DFG) (grant number DO 373/20-1 to SD), Federal Ministry of Education and Research (BMBF) Programme LiSyM-HCC (grant number PTJ-031L0257A to SD), the Stiftung Biomedizinische Alkohol-Forschung (grant number 73000350) and HiChol (01GM1904A to RL).

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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