Evaluation of Gremlin-1 as a therapeutic target in metabolic dysfunction-associated steatohepatitis
Gremlin-1 has been implicated in liver fibrosis in metabolic dysfunction-associated steatohepatitis (MASH) via inhibition of bone morphogenetic protein (BMP) signalling and has thereby been identified as a potential therapeutic target. Using rat in vivo and human in vitro and ex vivo model systems of MASH fibrosis, we show that neutralisation of Gremlin-1 activity with monoclonal therapeutic antibodies does not reduce liver inflammation or liver fibrosis. Still, Gremlin-1 was upregulated in human and rat MASH fibrosis, but expression was restricted to a small subpopulation of COL3A1/THY1 + myofibroblasts. Lentiviral overexpression of Gremlin-1 in LX-2 cells and primary hepatic stellate cells led to changes in BMP-related gene expression, which did not translate to increased fibrogenesis. Furthermore, we show that Gremlin-1 binds to heparin with high affinity, which prevents Gremlin-1 from entering systemic circulation, prohibiting Gremlin-1-mediated organ crosstalk. Overall, our findings suggest a redundant role for Gremlin-1 in the pathogenesis of liver fibrosis, which is unamenable to therapeutic targeting.
Authors
- Jan Fleckner
- Jenny Norlin (ORCID: https://orcid.org/0000-0002-4825-6975)
- Svend Poulsen (ORCID: https://orcid.org/0000-0002-5010-6992)
- Helle Demuth
- Mikkel Parsberg Werge (ORCID: https://orcid.org/0000-0002-9980-1072)
- Elisabeth D. Galsgaard (ORCID: https://orcid.org/0000-0002-0584-3803)
- Chris J. Weston (ORCID: https://orcid.org/0000-0002-9651-1264)
- Andreas Hald (ORCID: https://orcid.org/0009-0009-7778-5073)
- Philip N. Newsome (ORCID: https://orcid.org/0000-0001-6085-3652)
- Mogens Vyberg (ORCID: https://orcid.org/0000-0002-6392-9517)
- Morten G. Rasch (ORCID: https://orcid.org/0000-0003-4319-4338)
- Peder Lisby Nørby
- Paul M. Horn (ORCID: https://orcid.org/0000-0002-8755-7703)
- Morten Fog-Tonnesen (ORCID: https://orcid.org/0000-0001-5943-8558)
- Birgitte Martine Viuff (ORCID: https://orcid.org/0000-0002-1676-2531)
- Kasper Almholt (ORCID: https://orcid.org/0000-0002-9250-514X)
- Emma L. Shepherd (ORCID: https://orcid.org/0000-0002-1345-1746)
- Marco R Rink (ORCID: https://orcid.org/0000-0001-8741-8466)
- Ellie Northall (ORCID: https://orcid.org/0000-0003-4694-2071)
- Franziska Zosel
- Patricia F. Lalor (ORCID: https://orcid.org/0000-0001-8733-5273)
- Lise Lotte Gluud
Institutions
- University Hospitals Birmingham NHS Foundation Trust (GB)
- King's College London (GB)
- Hvidovre Hospital (DK)
- Copenhagen University Hospital (DK)
- National Institute for Health and Care Research (GB)
- Novo Nordisk (Switzerland) (CH)
- Novo Nordisk (United Kingdom) (GB)
- Institute of Immunology (HR)
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
- Novo Nordisk (Germany) (DE)
- King's College Hospital (GB)
- Charité - Universitätsmedizin Berlin (DE)
- University of Birmingham (GB)
- Aalborg University (DK)
Publication Details
- Journal
- eLife
- Published
- 2024-10-03
- DOI
- https://doi.org/10.7554/elife.95185.2
- Citations
- 2
- Primary Topic
- Liver Disease Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 0.77