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Bone morphogenetic protein 8B promotes the progression of non-alcoholic steatohepatitis

Authors
  • Vacca, M
  • Leslie, J
  • Virtue, S
  • Lam, BYH
  • Govaere, O
  • Tiniakos, D
  • Snow, S
  • Davies, S
  • Petkevicius, K
  • Tong, Z
  • Peirce, V
  • Nielsen, MJ
  • Ament, Z
  • Li, W
  • Kostrzewski, T
  • Leeming, DJ
  • Ratziu, V
  • Allison, MED
  • Anstee, QM
  • Griffin, JL
  • And 2 more
Publication Date
Apr 24, 2020
Source
Spiral - Imperial College Digital Repository
Keywords
License
Unknown

Abstract

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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