Bone morphogenetic protein 8B promotes the progression of non-alcoholic steatohepatitis.
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Non-alcoholic steatohepatitis (NASH) is characterized by lipotoxicity, inflammation and fibrosis, ultimately leading to end-stage liver disease. The molecular mechanisms promoting NASH are poorly understood, and treatment options are limited. Here, we demonstrate that hepatic expression of bone morphogenetic protein 8B (BMP8B), a member of the transforming growth factor beta (TGFβ)-BMP superfamily, increases proportionally to disease stage in people and animal models with NASH. BMP8B signals via both SMAD2/3 and SMAD1/5/9 branches of the TGFβ-BMP pathway in hepatic stellate cells (HSCs), promoting their proinflammatory phenotype. In vivo, the absence of BMP8B prevents HSC activation, reduces inflammation and affects the wound-healing responses, thereby limiting NASH progression. Evidence is featured in primary human 3D microtissues modelling NASH, when challenged with recombinant BMP8. Our data show that BMP8B is a major contributor to NASH progression. Owing to the near absence of BMP8B in healthy livers, inhibition of BMP8B may represent a promising new therapeutic avenue for NASH treatment.
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2522-5812
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Medical Research Council (MR/P01836X/1)
European Commission Horizon 2020 (H2020) Societal Challenges (634413)
Medical Research Council (MC_PC_13030)
Wellcome Trust (100574/Z/12/Z)
British Heart Foundation (None)
Medical Research Council (MC_UU_12012/5)
British Heart Foundation (RG/18/7/33636)
MRC (Unknown)
European Commission and European Federation of Pharmaceutical Industries and Associations (EFPIA) FP7 Innovative Medicines Initiative (IMI) (1153372)
Medical Research Council (MC_UU_12012/2)
British Heart Foundation (None)
British Heart Foundation (PG/15/39/31519)
British Heart Foundation (PG/17/1/32532)
MRC (MC_UU_00014/2)
MRC (MC_UU_00014/5)
Medical Research Council (G0802051)
Medical Research Council (G0400192)
Medical Research Council (MC_PC_12012)