Activator protein 1 transcription factor fos-related antigen 1 (fra-1) is dispensable for murine liver fibrosis, but modulates xenobiotic metabolism

Authors

  • Sebastian C. Hasenfuss,

    1. Genes, Development and Disease Group, F-BBVA Cancer Cell Biology Programme, National Cancer Research Centre (CNIO), Madrid, Spain
    2. University of Freiburg, Faculty of Biology, Freiburg, Germany
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  • Latifa Bakiri,

    1. Genes, Development and Disease Group, F-BBVA Cancer Cell Biology Programme, National Cancer Research Centre (CNIO), Madrid, Spain
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  • Martin K. Thomsen,

    1. Genes, Development and Disease Group, F-BBVA Cancer Cell Biology Programme, National Cancer Research Centre (CNIO), Madrid, Spain
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  • Rainer Hamacher,

    1. Genes, Development and Disease Group, F-BBVA Cancer Cell Biology Programme, National Cancer Research Centre (CNIO), Madrid, Spain
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  • Erwin F. Wagner

    Corresponding author
    1. Genes, Development and Disease Group, F-BBVA Cancer Cell Biology Programme, National Cancer Research Centre (CNIO), Madrid, Spain
    • Address reprint requests to: E.F. Wagner, Genes, Development and Disease Group, F-BBVA-CNIO Cancer Cell Biology Programme, Spanish National Cancer Research Centre, Melchor Fernandez Almagro 3, 28029 Madrid. Spain. E-mail: ewagner@cnio.es; fax: +34-912-246-980

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  • See Editorial on Page 19

    Potential conflict of interest: Nothing to report.

Abstract

The Activator Protein 1 (AP-1) transcription factor subunit Fos-related antigen 1 (Fra-1) has been implicated in liver fibrosis. Here we used loss-of-function as well as switchable, cell type-specific, gain-of-function alleles for Fra-1 to investigate the relevance of Fra-1 expression in cholestatic liver injury and fibrosis. Our results indicate that Fra-1 is dispensable in three well-established, complementary models of liver fibrosis. However, broad Fra-1 expression in adult mice results in liver fibrosis, which is reversible, when ectopic Fra-1 is switched off. Interestingly, hepatocyte-specific Fra-1 expression is not sufficient to trigger the disease, although Fra-1 expression leads to dysregulation of fibrosis-associated genes. Both opn and cxcl9 are controlled by Fra-1 in gain-of-function and loss-of-function experiments. Importantly, Fra-1 attenuates liver damage in the 3,5-diethoxycarbonyl-1,4-dihydrocollidine-feeding cholestatic liver injury model. Strikingly, manipulating Fra-1 expression affects genes involved in hepatic transport and detoxification, in particular glutathione S-transferases. Molecular analyses indicate that Fra-1 binds to the promoters of cxcl9 and gstp1 in vivo. Furthermore, loss of Fra-1 sensitizes, while hepatic Fra-1 expression protects from acetaminophen-induced liver damage, a paradigm for glutathione-mediated acute liver failure. Conclusion: These data define a novel function of Fra-1/AP-1 in modulating the expression of detoxification genes and the adaptive response of the liver to bile acids/xenobiotic overload. (Hepatology 2014;58:261–273)

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