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Activation of Mir-29a in Activated Hepatic Stellate Cells Modulates Its Profibrogenic Phenotype through Inhibition of Histone Deacetylases 4.

ABSTRACT: Recent studies have shown that microRNA-29 (miR-29) is significantly decreased in liver fibrosis and that its downregulation influences the activation of hepatic stellate cells (HSCs). In addition, inhibition of the activity of histone deacetylases 4 (HDAC4) has been shown to strongly reduce HSC activation in the context of liver fibrosis.In this study, we examined whether miR-29a was involved in the regulation of HDAC4 and modulation of the profibrogenic phenotype in HSCs.We employed miR-29a transgenic mice (miR-29aTg mice) and wild-type littermates to clarify the role of miR-29a in cholestatic liver fibrosis, using the bile duct-ligation (BDL) mouse model. Primary HSCs from both mice were treated with a miR-29a mimic and antisense inhibitor in order to analyze changes in profibrogenic gene expression and HSC activation using real-time quantitative RT-PCR, immunofluorescence staining, western blotting, and cell proliferation and migration assays.After BDL, overexpression of miR-29a decreased collagen-1?1, HDAC4 and activated HSC markers of glial fibrillary acidic protein expression in miR-29aTg mice compared to wild-type littermates. Overexpression of miR-29a and HDAC4 RNA-interference decreased the expression of fibrotic genes, HDAC4 signaling, and HSC migration and proliferation. In contrast, knockdown of miR-29a with an antisense inhibitor increased HDAC4 function, restored HSC migration, and accelerated HSC proliferation.Our results indicate that miR-29a ameliorates cholestatic liver fibrosis after BDL, at least partially, by modulating the profibrogenic phenotype of HSCs through inhibition of HDAC4 function.

SUBMITTER: Huang YH

PROVIDER: S-EPMC4549141 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Activation of Mir-29a in Activated Hepatic Stellate Cells Modulates Its Profibrogenic Phenotype through Inhibition of Histone Deacetylases 4.

Huang Ying-Hsien YH Tiao Mao-Meng MM Huang Li-Tung LT Chuang Jiin-Haur JH Kuo Kuang-Che KC Yang Ya-Ling YL Wang Feng-Sheng FS

PloS one 20150825 8

<h4>Background</h4>Recent studies have shown that microRNA-29 (miR-29) is significantly decreased in liver fibrosis and that its downregulation influences the activation of hepatic stellate cells (HSCs). In addition, inhibition of the activity of histone deacetylases 4 (HDAC4) has been shown to strongly reduce HSC activation in the context of liver fibrosis.<h4>Objectives</h4>In this study, we examined whether miR-29a was involved in the regulation of HDAC4 and modulation of the profibrogenic ph ...[more]

PMID: 26305546

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Project description:Background & aimsActivation of Kupffer cells and recruitment of monocytes are key events in fibrogenesis. These cells release soluble mediators which induce the activation of hepatic stellate cells (HSCs), the main fibrogenic cell type within the liver. Mer tyrosine kinase (MerTK) signaling regulates multiple processes in macrophages and has been implicated in the pathogenesis of non-alcoholic steatohepatitis-related fibrosis. In this study, we explored if MerTK activation in macrophages influences the profibrogenic phenotype of HSCs.MethodsMacrophages were derived from THP-1 cells or differentiated from peripheral blood monocytes towards MerTK+/CD206+/CD163+/CD209- macrophages. The role of MerTK was assessed by pharmacologic and genetic inhibition. HSC migration was determined in Boyden chambers, viability was measured by the MTT assay, and proliferation was evaluated by the BrdU incorporation assay.ResultsGas-6 induced MerTK phosphorylation and Akt activation in macrophages, and these effects were inhibited by UNC569. During polarization, MerTK+/CD206+/CD163+/CD209- macrophages exhibited activation of STAT3, ERK1/2, p38 and increased expression of VEGF-A. Activation of MerTK in THP-1 macrophages induced a secretome which promoted a significant increase in migration, proliferation, viability and expression of profibrogenic factors in HSCs. Similarly, conditioned medium from MerTK+ macrophages induced a significant increase in cell migration, proliferation, STAT3 and p38 phosphorylation and upregulation of IL-8 expression in HSCs. Moreover, conditioned medium from Gas-6-stimulated Kupffer cells induced a significant increase in HSC proliferation. These effects were specifically related to MerTK expression and activity in macrophages, as indicated by pharmacologic inhibition and knockdown experiments.ConclusionsMerTK activation in macrophages modifies the secretome to promote profibrogenic features in HSCs, implicating this receptor in the pathogenesis of hepatic fibrosis.Lay summaryFibrosis represents the process of scarring occurring in patients with chronic liver diseases. This process depends on production of scar tissue components by a specific cell type, named hepatic stellate cells, and is regulated by interaction with other cells. Herein, we show that activation of MerTK, a receptor present in a population of macrophages, causes the production of factors that act on hepatic stellate cells, increasing their ability to produce scar tissue.

Dataset Information

Activation of Mir-29a in Activated Hepatic Stellate Cells Modulates Its Profibrogenic Phenotype through Inhibition of Histone Deacetylases 4.

Publications

Activation of Mir-29a in Activated Hepatic Stellate Cells Modulates Its Profibrogenic Phenotype through Inhibition of Histone Deacetylases 4.

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