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PU.1-deficient mice are resistant to thioacetamide-induced hepatic fibrosis: PU.1 finely regulates Sirt1 expression via transcriptional promotion of miR-34a and miR-29c in hepatic stellate cells.

Abstract：

:PU box binding protein (PU.1) is a critical transcription factor involved in many pathological processes. However, its exact role in activation of hepatic stellate cells (HSCs) and liver fibrosis was rarely reported. Here, we found that, in HSCs of PU.1+/- mice, Sirt1 mRNA expression was not changed but Sirt1 protein was significantly increased, suggesting its promoting role in Sirt1 translation. We then isolated HSCs from wild-type (WT) and PU.1+/- mice, and the pcDNA-PU.1 expression vector was transfected into PU.1+/- HSCs. We checked the levels of miR-34a and miR-29c, two Sirt1-targetting miRNAs, and protein levels of PU.1 and Sirt1. The results showed that miR-34a/-29c were significantly reduced and Sirt1 protein was increased in PU.1+/- HSCs, compared with WT HSCs. Besides, PU.1 overexpression inversed the reduction in miR-34a/-29c levels and the increase in Sirt1 protein in both PU.1+/- HSCs and WT HSCs. Additionally, ChIP-quantitive real-time PCR (qPCR) assay comfirmed that PU.1 was directly bound to both the promoter regions of miR-34a and miR-29c Importantly, PU.1 overexpression promoted the proliferation, migration, activation, oxidative stress and inflammatory response in WT HSCs, while the promotion could be inversed by either overexpression of Sirt1 or inhibition of miR-34a/-29c Moreover, animal model of liver fibrosis was established by intraperitoneal injections of thioacetamide (TAA) in WT and PU.1+/- mice, respectively. Compared with the WT mice, PU.1+/- mice displayed a lower fibrotic score, less collagen content, better liver function, and lower levels of oxidative stress and inflammatory response. In conclusion, PU.1 suppresses Sirt1 translation via transcriptional promotion of miR-34a/-29c, thus promoting Sirt1-mediated HSC activation and TAA-induced hepatic fibrosis.

journal_name

Biosci Rep

journal_title

Bioscience reports

authors

Liu Q,Zhang Y,Yang S,Wu Y,Wang J,Yu W,Liu Y

doi

10.1042/BSR20170926

subject

Has Abstract

pub_date

2017-12-12 00:00:00

issue

eissn

0144-8463

issn

1573-4935

pii

BSR20170926

journal_volume

pub_type

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PU.1-deficient mice are resistant to thioacetamide-induced hepatic fibrosis: PU.1 finely regulates Sirt1 expression via transcriptional promotion of miR-34a and miR-29c in hepatic stellate cells.