Myostatin regulates the fibrogenic phenotype of hepatic stellate cells via c-jun N-terminal kinase activation |
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Authors: | Wanda Delogu Alessandra Caligiuri Angela Provenzano Chiara Rosso Elisabetta Bugianesi Andrea Coratti Jose Macias-Barragan Sara Galastri Giovanni Di Maira Fabio Marra |
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Affiliation: | 1. Dipartimento di Medicina Sperimentale Clinica, University of Florence, Florence, Italy;2. Research Center Denothe, University of Florence, Florence, Italy;3. Dipartimento di Scienze Mediche, University of Turin, Turin, Italy;4. SOD Chirurgia Oncologia a indirizzo robotico, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy |
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Abstract: | Background & aimsMyostatin is mainly expressed in skeletal muscle, where it negatively regulates trophism. This myokine is implicated in the pathophysiology of nonalcoholic steatohepatitis, an emerging cause of liver fibrosis. In this study we explored the effects of myostatin on the biology of hepatic stellate cells.MethodsThe effects of myostatin were assessed both in LX-2 and in human primary stellate cells. Cell migration was determined in Boyden chambers. Activation of intracellular pathways was evaluated by Western blotting. Procollagen type 1 secretion was measured by enzyme immunoassay. The role of c-Jun N-terminal kinase was assessed by pharmacologic and genetic inhibition.ResultsActivin receptor-2B was up-regulated in livers of mice with experimental fibrosis, and detectable in human stellate cells. Serum myostatin levels increased in a model of acute liver injury. Myostatin reduced HSC proliferation, induced cell migration, and increased expression of procollagen type1, tissue inhibitor of metalloproteinase-1, and transforming growth factor-β1. Myostatin activated different signaling pathways, including c-Jun N-terminal kinase and Smad3. Genetic and/or pharmacologic inhibition of c-Jun N-terminal kinase activity significantly reduced cell migration and procollagen secretion in response to myostatin.ConclusionsActivation of activin receptor-2B by myostatin modulates the fibrogenic phenotype of human stellate cells, indicating that a myokine may be implicated in the pathogenesis of hepatic fibrosis. |
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Keywords: | Corresponding author: Dipartimento di Medicina Sperimentale e Clinica, University of Florence, Largo Brambilla, 3 Florence, I50134, Italy. ActR2B activin receptor-2B HSC hepatic stellate cells JNK c-Jun N-terminal kinase PDGF platelet-derived growth factor TGF transforming growth factor NAFLD nonalcoholic fatty liver disease NASH nonalcoholic steatohepatitis Hepatic fibrosis Myokines Metabolic syndrome Nonalcoholic steatohepatitis |
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