| First Author | Schulien I | Year | 2019 |
| Journal | Cell Death Differ | Volume | 26 |
| Issue | 9 | Pages | 1688-1699 |
| PubMed ID | 30778201 | Mgi Jnum | J:285537 |
| Mgi Id | MGI:6391475 | Doi | 10.1038/s41418-018-0239-8 |
| Citation | Schulien I, et al. (2019) The transcription factor c-Jun/AP-1 promotes liver fibrosis during non-alcoholic steatohepatitis by regulating Osteopontin expression. Cell Death Differ 26(9):1688-1699 |
| abstractText | Progression of non-alcoholic fatty liver disease (NAFLD) from steatosis to non-alcoholic steatohepatitis (NASH) is a key step of NASH pathogenesis. The AP-1 transcription factor c-Jun is an important regulator of hepatic stress responses, but its contribution to NASH pathogenesis remains poorly defined. We therefore addressed c-Jun expression in liver biopsies of patients with steatosis and NASH. The role of c-Jun during NASH pathogenesis was analyzed mechanistically in c-Jun mutant mice fed with a methionine- and choline-deficient diet (MCDD). Disease progression from steatosis to NASH in patients correlated with increased c-Jun expression in hepatocytes, while its expression in non-parenchymal liver cells (NPLCs) particularly correlated with fibrosis. Analysis of untreated and MCDD-fed mice lacking c-Jun in hepatocytes (c-Jun(li)) revealed that c-Jun promotes hepatocyte survival, thereby protecting against the regenerative ductular reaction (DR) of Sox9/Osteopontin (Opn) co-expressing NPLCs, expression of the Opn receptor CD44 and fibrosis, which were all exacerbated in c-Jun(li) mice. Since Opn and c-Jun were co-expressed by NPLCs in mice and patients with NASH, we wondered whether the increased fibrosis observed in c-Jun(li) mice could be rescued by additional c-Jun deletion in NPLCs (c-Jun(li*)). c-Jun(li*) mice with NASH indeed exhibited reduced expression of Opn and CD44 in NPLCs, impaired DR and reduced fibrosis. A similar phenotype was observed in Opn knockout mice, suggesting that the observed functions of c-Jun were indeed Opn-dependent. In conclusion, c-Jun expression correlates with disease progression from steatosis to NASH in patients and exerts cell-type-specific functions in mice: In hepatocytes, it promotes cell survival thereby limiting the DR and fibrogenesis. In NPLCs, it rather promotes the DR and fibrogenesis by regulating expression of Opn and CD44. |
