脂肪性肝炎
肝星状细胞
骨形态发生蛋白
促炎细胞因子
炎症
纤维化
脂毒性
脂肪肝
癌症研究
转化生长因子
生物
细胞生物学
转化生长因子β
生物信息学
医学
疾病
免疫学
病理
内分泌学
生物化学
基因
胰岛素抵抗
胰岛素
作者
Michèle Vacca,Jack Leslie,Samuel Virtue,Brian Lam,Olivier Govaere,Dina Tiniakos,Sophie Snow,Susan Davies,Kasparas Petkevicius,Zhen Tong,Vivian Peirce,Mette Juul Nielsen,Zsuzsanna Ament,Wei Li,Tomasz Kostrzewski,Diana Julie Leeming,Vlad Ratziu,Michael Allison,Quentin M. Anstee,Julian L. Griffin,Fiona Oakley,Antonio Vidal‐Puig
标识
DOI:10.1038/s42255-020-0214-9
摘要
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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