title: Activator Protein 1 transcription factor Fos-related antigen 1 (Fra-1) is dispensable for murine liver fibrosis, but modulates xenobiotic metabolism.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Genes, Development and Disease Group, F-BBVA Cancer Cell Biology Programme, National Cancer Research Centre (CNIO), Madrid, Spain; University of Freiburg, Faculty of Biology, Freiburg, Germany.
authors.forename: Sebastian C
authors.initials: SC
authors.lastname: Hasenfuss
authors.forename: Latifa
authors.initials: L
authors.lastname: Bakiri
authors.forename: Martin K
authors.initials: MK
authors.lastname: Thomsen
authors.forename: Rainer
authors.initials: R
authors.lastname: Hamacher
authors.forename: Erwin F
authors.initials: EF
authors.lastname: Wagner
mesh_terms: D000082:Acetaminophen / Q000506:poisoning; D000222:Adaptation, Physiological; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism; D054370:Chemokine CXCL9 / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D051549:Glutathione S-Transferase pi / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006706:Homeostasis; D008658:Inactivation, Metabolic; D007527:Isoenzymes / Q000378:metabolism; D008103:Liver Cirrhosis / Q000209:etiology* / Q000378:metabolism; D051379:Mice; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D015262:Xenobiotics / Q000378:metabolism; D000099169:Fos-Related Antigen 1
chemical_list: D000082:Acetaminophen; D001647:Bile Acids and Salts; D054370:Chemokine CXCL9; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D007527:Isoenzymes; D016760:Proto-Oncogene Proteins c-fos; D015262:Xenobiotics; D000099169:Fos-Related Antigen 1; C485969:Cxcl9 protein, mouse; C496557:Gstp1 protein, mouse; C119995:glutathione S-transferase alpha