
Gremlin-1은 대사 기능 장애 관련 지방간염 섬유화에서 중요한 역할을 하지 않는 것으로 나타났다.


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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.

### Competing Interest Statement

PH, PFL and CJW report research funding from Novo Nordisk through the University of Birmingham. JN, KA, BMV, EDG, AH, FZ, HD, SP, PLN, MGR, MFT are full-time employees of Novo Nordisk A/S. LLG has received consulting fees and payment or honoraria for lectures, presentations or manuscript writing from: Novo Nordisk, Pfizer, Gilead, AstraZeneca, Norgine, Sobi, Becton Dickinson, Alexion and Vingmed. PNN reports consulting for Boehringer Ingelheim, Novo Nordisk, Intercept, Gilead, Poxel Pharmaceuticals and BMS on behalf of the University of Birmingham and research grants from Novo Nordisk and Boehringer Ingelheim. MV, MRR, MPW, ES, and EN report no conflicts of interest related to this manuscript.

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

대사-기능-장애-관련-지방간염에서-gremlin-1의-치료-표적으로서의-평가


대사 기능 장애 관련 지방간염에서 Gremlin-1의 치료 표적으로서의 평가
