Martin Kristian Thomsen

Activator Protein 1 transcription factor Fos-related antigen 1 (Fra-1) is dispensable for murine liver fibrosis, but modulates xenobiotic metabolism

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

DOI

  • Sebastian C Hasenfuss, Genes, Development, and Disease Group, F-BBVA Cancer Cell Biology Programme, National Cancer Research Centre (CNIO), 28029 Madrid, Spain; Faculty Biology, University of Freiburg, 79104 Freiburg, Germany.
  • ,
  • Latifa Bakiri
  • ,
  • Martin K Thomsen
  • Rainer Hamacher
  • ,
  • Erwin F Wagner

UNLABELLED: 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.

Original languageEnglish
JournalHepatology
Volume59
Issue1
Pages (from-to)261-73
Number of pages13
ISSN0270-9139
DOIs
Publication statusPublished - Jan 2014

    Research areas

  • Acetaminophen, Adaptation, Physiological, Animals, Bile Acids and Salts, Chemical and Drug Induced Liver Injury, Chemokine CXCL9, Disease Models, Animal, Gene Expression Regulation, Glutathione S-Transferase pi, Glutathione Transferase, Hepatocytes, Homeostasis, Inactivation, Metabolic, Isoenzymes, Liver Cirrhosis, Mice, Proto-Oncogene Proteins c-fos, Xenobiotics, Journal Article, Research Support, Non-U.S. Gov't

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