| First Author | Hasenfuss SC | Year | 2014 |
| Journal | Hepatology | Volume | 59 |
| Issue | 1 | Pages | 261-73 |
| PubMed ID | 23703832 | Mgi Jnum | J:213764 |
| Mgi Id | MGI:5585721 | Doi | 10.1002/hep.26518 |
| Citation | Hasenfuss SC, et al. (2014) Activator Protein 1 transcription factor Fos-related antigen 1 (Fra-1) is dispensable for murine liver fibrosis, but modulates xenobiotic metabolism. Hepatology 59(1):261-73 |
| abstractText | 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. |
