Evaluation of Gremlin-1 as a therapeutic target in metabolic dysfunction-associated steatohepatitis

Paul Horn, Jenny Norlin, Kasper Almholt, Birgitte M Viuff, Elisabeth D Galsgaard, Andreas Hald, Franziska Zosel, Helle Demuth, Svend Poulsen, Peder L Norby, Morten G Rasch, Mogens Vyberg, Jan Fleckner, Mikkel Parsberg Werge, Lise Lotte Gluud, Marco R Rink, Emma Shepherd, Ellie Northall, Patricia F Lalor, Chris J WestonMorten Fog-Tonnesen, Philip N Newsome*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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Abstract

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.
Original languageEnglish
Article numberRP95185
Number of pages27
JournaleLife
Volume13
DOIs
Publication statusPublished - 3 Oct 2024

Keywords

  • metabolic dysfunction-associated steatohepatitis
  • Human
  • Mouse
  • bone morphogenetic proteins
  • Rat
  • NAFLD
  • Gremlin-1
  • metabolic dysfunction-associated steatotic liver disease
  • liver fibrosis

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