Evaluation of Gremlin-1 as a therapeutic target in metabolic dysfunction-associated steatohepatitis.
Horn, Paul Norlin, Jenny Almholt, Kasper Viuff, Birgitte M Galsgaard, Elisabeth D Hald, Andreas Zosel, Franziska Demuth, Helle Poulsen, Svend Norby, Peder L
Horn, Paul
Norlin, Jenny
Almholt, Kasper
Viuff, Birgitte M
Galsgaard, Elisabeth D
Hald, Andreas
Zosel, Franziska
Demuth, Helle
Poulsen, Svend
Norby, Peder L
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2024-10-03
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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.
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Horn P, Norlin J, Almholt K, Viuff BM, Galsgaard ED, Hald A, Zosel F, Demuth H, Poulsen S, Norby PL, Rasch MG, Vyberg M, Fleckner J, Werge MP, Gluud LL, Rink MR, Shepherd E, Northall E, Lalor PF, Weston CJ, Fog-Tonnesen M, Newsome PN. Evaluation of Gremlin-1 as a therapeutic target in metabolic dysfunction-associated steatohepatitis. Elife. 2024 Oct 3;13:RP95185. doi: 10.7554/eLife.95185.
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