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J Hepatol. 2013 Mar;58(3):522-8. doi: 10.1016/j.jhep.2012.11.011. Epub 2012 Nov 21.

miR-122 regulates collagen production via targeting hepatic stellate cells and suppressing P4HA1 expression.

Author information

  • 1Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, United States. jil35@pitt.edu

Abstract

BACKGROUND & AIMS:

MicroRNAs (miRNAs) have been shown to be involved in many biological processes by affecting their target gene expression. miR-122 has been extensively studied in hepatocarcinogenesis. However, the role of miR-122 in liver fibrosis remains unknown.

METHODS:

The mRNA expression levels of miR-122, prolyl 4-hydroxylase subunit alpha-1 (P4HA1), and CCAAT/enhancer binding protein alpha (C/EBPα) were assessed by real-time PCR. The protein expression levels of P4HA1, C/EBPα and collagen, type I, alpha 1 (COL1A1) were analyzed by Western blot and immunofluorescence. MTT assay was used to assess cell proliferation. Chromatin immunoprecipitation (ChIP) assay was used to examine the binding activity of C/EBPα to miR-122 promoter.

RESULTS:

miR-122 expression was significantly reduced in transactivated HSCs and in the livers of mice treated with CCl(4). Overexpression of miR-122 inhibited the proliferation of LX2 cells. We also demonstrated that P4HA1 was a target gene of miR-122. The mRNA expression level of PAHA1 inversely correlated with that of miR-122 in HSCs and in the mouse liver. Overexpression of miR-122 markedly attenuated the expression of P4HA1 via targeting a binding site located at 3'-UTR of P4HA1 mRNA. We further showed that miR-122 overexpression led to decreased collagen maturation and ECM production. Finally, the binding activity of C/EBPα to miR-122 promoter was significantly decreased in activated HSCs.

CONCLUSIONS:

Our study suggests that miR-122 may play an important role in negatively regulating collagen production in HSCs and that targeted expression of miR-122 in HSCs may represent a new strategy for the treatment of liver fibrosis.

Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

PMID:
23178710
[PubMed - indexed for MEDLINE]
PMCID:
PMC3619187
Free PMC Article
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