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

Research output: Contribution to journalArticlepeer-review

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 number95185
Number of pages27
JournaleLife
Volume13
Early online date26 Jun 2024
DOIs
Publication statusPublished - 3 Oct 2024

Bibliographical note

Copyright © Horn et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

Keywords

  • Animals
  • Intercellular Signaling Peptides and Proteins/metabolism
  • Humans
  • Rats
  • Liver Cirrhosis/metabolism
  • Fatty Liver/metabolism
  • Hepatic Stellate Cells/metabolism
  • Disease Models, Animal
  • Male
  • Cytokines

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