1. Myostatin regulates the fibrogenic phenotype of hepatic stellate cells via c-jun N-terminal kinase activation.
- Author
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Delogu W, Caligiuri A, Provenzano A, Rosso C, Bugianesi E, Coratti A, Macias-Barragan J, Galastri S, Di Maira G, and Marra F
- Subjects
- Animals, Cell Line, Cells, Cultured, Disease Models, Animal, Enzyme Activation, Humans, Liver pathology, Mice, Mice, Inbred C57BL, Phenotype, Signal Transduction, Tissue Inhibitor of Metalloproteinase-1 metabolism, Transforming Growth Factor beta1 metabolism, Activin Receptors, Type II metabolism, Hepatic Stellate Cells metabolism, JNK Mitogen-Activated Protein Kinases metabolism, Liver Cirrhosis metabolism, Myostatin blood
- Abstract
Background & Aims: Myostatin 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., Methods: The 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., Results: Activin 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., Conclusions: Activation 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., (Copyright © 2019 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2019
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