Abstract
BackgroundRecent 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.ObjectivesIn this study, we examined whether miR-29a was involved in the regulation of HDAC4 and modulation of the profibrogenic phenotype in HSCs.MethodsWe 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.ResultsAfter BDL, overexpression of miR-29a decreased collagen-1α1, 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.ConclusionsOur 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.
Highlights
Persistent liver injury due to cholestasis and hepatitis may result in liver fibrosis that engages a range of cell types [1, 2]
After bile duct ligation (BDL), overexpression of miR-29a decreased collagen-1α1, histone deacetylases 4 (HDAC4) and activated hepatic stellate cells (HSCs) markers of glial fibrillary acidic protein expression in miR-29aTg mice compared to wild-type littermates
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
Summary
Persistent liver injury due to cholestasis and hepatitis may result in liver fibrosis that engages a range of cell types [1, 2]. Following acute or chronic liver injury of any etiology, hepatic stellate cells (HSCs) are activated and undergo morphologic and functional trans-differentiation, transforming from vitamin A-storing cells into contractile myofibroblastic cells responsible for extracellular matrix (ECM) production in the injured liver [1,2,3]. Recent studies have shown that the expression of miR-132 and miR-29, which consists of miR-29a, miR-29b, and miR-29c, are significantly decreased in fibrotic livers, as demonstrated in human liver cirrhosis as well as in two different models of liver injury induced by bile duct ligation (BDL) and carbon tetrachloride (CCl4) [5]. 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). Inhibition of the activity of histone deacetylases 4 (HDAC4) has been shown to strongly reduce HSC activation in the context of liver fibrosis.
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