Activation of miR-29a in activated hepatic stellate cells modulates its profibrogenic phenotype through inhibition of histone deacetylases 4

Ying Hsien Huang, Mao Meng Tiao, Li Tung Huang, Jiin Haur Chuang, Kuang Che Kuo, Ya Ling Yang, Feng Sheng Wang

Research output: Contribution to journalJournal Article peer-review

46 Scopus citations

Abstract

Background: 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. Objectives: In this study, we examined whether miR-29a was involved in the regulation of HDAC4 and modulation of the profibrogenic phenotype in HSCs. Methods: 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. Results: After BDL, overexpression of miR-29a decreased collagen-1 7alpha;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. Conclusions: 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.

Original languageEnglish
Article numbere0136453
JournalPLoS ONE
Volume10
Issue number8
DOIs
StatePublished - 25 08 2015

Bibliographical note

Publisher Copyright:
© 2015 Huang et al.

Fingerprint

Dive into the research topics of 'Activation of miR-29a in activated hepatic stellate cells modulates its profibrogenic phenotype through inhibition of histone deacetylases 4'. Together they form a unique fingerprint.

Cite this