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Research ArticleArticle

Roles of microRNA-29a in the Antifibrotic Effect of Farnesoid X Receptor in Hepatic Stellate Cells

Jiang Li, Yifei Zhang, Ramalinga Kuruba, Xiang Gao, Chandrashekhar R. Gandhi, Wen Xie and Song Li
Molecular Pharmacology July 2011, 80 (1) 191-200; DOI: https://doi.org/10.1124/mol.110.068247
Jiang Li
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Yifei Zhang
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Ramalinga Kuruba
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Xiang Gao
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Chandrashekhar R. Gandhi
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Wen Xie
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Song Li
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This article has a correction. Please see:

  • Clarification: “Roles of micro-RNA-29a in the Antifibrotic Effect of Farnesoid X Receptor on Hepatic Stellate Cells” - August 01, 2012

Abstract

Liver fibrosis is a chronic disorder that is characterized by an alteration of the balance between fibrogenesis and fibrinolysis, which results in accumulation of excessive amounts of extracellular matrix (ECM) and distortion of the normal liver architecture. The activation and transformation of quiescent hepatic stellate cells (HSCs) into myofibroblast-like cells constitute a major mechanism for the increased production of ECM in the liver. The nuclear receptor farnesoid X receptor (FXR) shows potent antifibrotic activity in HSCs and protects animals in rodent models of liver fibrosis. However, the detailed mechanism remains incompletely understood. In this study, we report that treatment with 3-[2-[2-chloro-4-[[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methoxy]phenyl]ethenyl]benzoic acid (GW4064), a synthetic FXR ligand, led to up-regulation of microRNA-29a (miR-29a) in HSCs isolated from wild-type mice, rats, and humans but not from FXR(−/−) mice. miR-29a seems to play an inhibitory role in the regulation of ECM production because of the following: 1) transfection of HSCs with miR-29a mimic resulted in drastic down-regulation of the mRNA expression of several genes that encode ECM proteins; and 2) miR-29a significantly inhibited the expression of a reporter expression plasmid that contains the 3′-untranslated region of the corresponding ECM genes. Our results suggest that miR-29a is a FXR target gene because miR-29a promoter activity was significantly increased by pharmacologic or genetic activation of FXR. Functional analysis of human miR-29a promoter identified an imperfect inverted repeat spaced by one nucleotide DNA motif, inverted repeat-1 (5′-AGGTCAcAGACCT-3′), as a likely FXR-responsive element that is involved in miR-29a regulation. Our study uncovers a new mechanism by which FXR negatively regulates the expression of ECM in HSCs.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This work was supported by the National Institutes of Health National Heart, Lung and Blood Institute [Grants HL68688, HL091828-01]; and in part by a grant from University of Pittsburgh Central Research Development Fund.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.110.068247.

  • ABBREVIATIONS:

    ECM
    extracellular matrix
    TGF
    transforming growth factor
    HSC
    hepatic stellate cell
    FXR
    farnesoid X receptor
    SHP
    short heterodimer partner
    miRNA
    microRNA
    UTR
    untranslated region
    AP-1
    activator protein 1
    NF-κB
    nuclear factor-κB
    GW4064
    3-[2-[2-chloro-4-[[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methoxy]phenyl]ethenyl]benzoic acid
    FXRE
    FXR response element
    RT
    reverse transcription
    PCR
    polymerase chain reaction
    COL1A1
    collagen 1A1
    kb
    kilobase(s)
    IR-1
    inverted repeat spaced by one nucleotide
    COL3A1
    collagen 3A1
    ELN1
    elastin-1
    DMSO
    dimethyl sulfoxide
    RXR
    retinoid X receptor
    ChIP
    chromatin immunoprecipitation.

  • Received August 16, 2010.
  • Accepted April 21, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 80 (1)
Molecular Pharmacology
Vol. 80, Issue 1
1 Jul 2011
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Research ArticleArticle

Roles of microRNA-29a in the Antifibrotic Effect of Farnesoid X Receptor in Hepatic Stellate Cells

Jiang Li, Yifei Zhang, Ramalinga Kuruba, Xiang Gao, Chandrashekhar R. Gandhi, Wen Xie and Song Li
Molecular Pharmacology July 1, 2011, 80 (1) 191-200; DOI: https://doi.org/10.1124/mol.110.068247

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Research ArticleArticle

Roles of microRNA-29a in the Antifibrotic Effect of Farnesoid X Receptor in Hepatic Stellate Cells

Jiang Li, Yifei Zhang, Ramalinga Kuruba, Xiang Gao, Chandrashekhar R. Gandhi, Wen Xie and Song Li
Molecular Pharmacology July 1, 2011, 80 (1) 191-200; DOI: https://doi.org/10.1124/mol.110.068247
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