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

Autor: Julian L. Griffin, Jack Leslie, Quentin M. Anstee, Sophie Snow, Susan E. Davies, Vivian Peirce, Brian Y.H. Lam, Dina Tiniakos, Mette Juul Nielsen, Zhen Tong, Fiona Oakley, Olivier Govaere, Michael Allison, Diana Julie Leeming, Tomasz Kostrzewski, Michele Vacca, Antonio Vidal-Puig, Zsuzsanna Ament, Samuel Virtue, Vlad Ratziu, Wei Li, Kasparas Petkevicius
Přispěvatelé: Medical Research Council, Medical Research Council (MRC), Vacca, Michele [0000-0002-1973-224X], Leslie, Jack [0000-0001-6443-2396], Govaere, Olivier [0000-0002-4426-6930], Petkevicius, Kasparas [0000-0003-2295-6065], Ament, Zsuzsanna [0000-0002-0316-4348], Li, Wei [0000-0002-1924-3120], Kostrzewski, Tomasz [0000-0001-6309-628X], Anstee, Quentin M [0000-0002-9518-0088], Vidal-Puig, Antonio [0000-0003-4220-9577], Apollo - University of Cambridge Repository
Rok vydání: 2020
Předmět:
BLOOD
SCORING SYSTEM
Endocrinology
Diabetes and Metabolism
Smad Proteins
Mice
0302 clinical medicine
Non-alcoholic Fatty Liver Disease
Transforming Growth Factor beta
FIBROSIS
GENE-EXPRESSION
0303 health sciences
biology
Carbon Tetrachloride Poisoning
Recombinant Proteins
Liver regeneration
3. Good health
Lipotoxicity
030220 oncology & carcinogenesis
Bone Morphogenetic Proteins
GROWTH
LIVER-INJURY
medicine.symptom
Life Sciences & Biomedicine
Inflammation
Diet
High-Fat
Bone morphogenetic protein
digestive system
Proinflammatory cytokine
Endocrinology & Metabolism
03 medical and health sciences
Physiology (medical)
Hepatic Stellate Cells
Internal Medicine
medicine
Animals
Humans
030304 developmental biology
Wound Healing
Science & Technology
FATTY-ACID
OSTEOPROTEGERIN
nutritional and metabolic diseases
Cell Biology
Transforming growth factor beta
medicine.disease
digestive system diseases
Liver Regeneration
Mice
Inbred C57BL
MODEL
BMP8B
Diet
Western
biology.protein
Hepatic stellate cell
Cancer research
Steatohepatitis
Zdroj: Nature Metabolism. 2:514-531
ISSN: 2522-5812
DOI: 10.1038/s42255-020-0214-9
Popis: 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.
Databáze: OpenAIRE
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