Τίτλος:
Bone morphogenetic protein 8B promotes the progression of non-alcoholic steatohepatitis
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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. © 2020, The Author(s), under exclusive licence to Springer Nature Limited.
Συγγραφείς:
Vacca, M.
Leslie, J.
Virtue, S.
Lam, B.Y.H.
Govaere, O.
Tiniakos, D.
Snow, S.
Davies, S.
Petkevicius, K.
Tong, Z.
Peirce, V.
Nielsen, M.J.
Ament, Z.
Li, W.
Kostrzewski, T.
Leeming, D.J.
Ratziu, V.
Allison, M.E.D.
Anstee, Q.M.
Griffin, J.L.
Oakley, F.
Vidal-Puig, A.
Περιοδικό:
Nature Metabolism
Εκδότης:
Lithuanian Nature Research Centre
Λέξεις-κλειδιά:
bone morphogenetic protein; bone morphogenetic protein 8B; gelatinase B; inflammasome; Smad1 protein; Smad2 protein; Smad3 protein; Smad5 protein; transforming growth factor beta; unclassified drug; vasculotropin; BMP8B protein, human; Bmp8b protein, mouse; bone morphogenetic protein; recombinant protein; Smad protein; transforming growth factor beta, AML12 cell line; animal experiment; animal model; animal tissue; Article; bioinformatics; calorimetry; carbon tetrachloride-induced liver injury; cell activation; cell differentiation; cell isolation; cell proliferation; controlled study; energy expenditure; gene expression; glucose metabolism; hepatic stellate cell; histopathology; human; human cell; immunofluorescence; immunohistochemistry; in situ hybridization; lipid metabolism; mouse; nonalcoholic fatty liver; nonhuman; partial hepatectomy; phenotype; phosphoproteomics; prevalence; priority journal; protein expression; proteomics; reverse transcription polymerase chain reaction; risk factor; RNA extraction; RNA sequence; RNA sequencing; signal transduction; transcriptomics; upregulation; animal; C57BL mouse; drug effect; genetics; inflammation; intoxication; lipid diet; liver regeneration; metabolism; nonalcoholic fatty liver; Western diet; wound healing, Animals; Bone Morphogenetic Proteins; Carbon Tetrachloride Poisoning; Diet, High-Fat; Diet, Western; Hepatic Stellate Cells; Humans; Inflammation; Liver Regeneration; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Recombinant Proteins; Smad Proteins; Transforming Growth Factor beta; Wound Healing
DOI:
10.1038/s42255-020-0214-9
