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

Horn, P.; Norlin, J.; Almholt, K.; Viuff, B. M.; Galsgaard, E. D.; Hald, A.; Zosel, F.; Demuth, H.; Poulsen, S.; Norby, P. L.; Rasch, M. G.; Vyberg, M.; Rink, M. R.; Shepherd, E.; Northall, E.; Lalor, P. F.; Weston, C. J.; Fog-Tonnesen, M.; Newsome, P.

doi:10.1101/2024.01.03.574043

bioRxiv · 10.1101/2024.01.03.574043

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

Horn, P.·Norlin, J.·Almholt, K.·Viuff, B. M.·Galsgaard, E. D.·Hald, A.·Zosel, F.·Demuth, H.·Poulsen, S.·Norby, P. L.·Rasch, M. G.·Vyberg, M.·Rink, M. R.·Shepherd, E.·Northall, E.·Lalor, P. F.·Weston, C. J.·Fog-Tonnesen, M.·Newsome, P.

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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, B. M., Galsgaard, E. D., Hald, A., Zosel, F., Demuth, H., Poulsen, S., Norby, P. L., Rasch, M. G., Vyberg, M., Rink, M. R., Shepherd, E., Northall, E., Lalor, P. F., Weston, C. J., Fog-Tonnesen, M., Newsome, P.. 2024-01-05. Evaluation of Gremlin-1 as a therapeutic target in metabolic dysfunction-associated steatohepatitis. https://doi.org/10.1101/2024.01.03.574043

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