The transcription factor c-Jun/AP-1 promotes liver fibrosis during non-alcoholic steatohepatitis by regulating Osteopontin expression

Abstract

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.

A single-cell gene regulatory network inference method for identifying complex regulatory dynamics across cell phenotypes

“…In SimiC, on the contrary, there is a clear distinction between the peak obtained in state 0 and the other states. The higher peak value in state 0 also shows that the TF JUND is more active in early stages and promotes hepatocyte proliferation, which is confirmed in the existing literature [31,5]. Such separation can also be easily seen in the wAUC colored UMAP plots, as SCENIC has only a few outliers highlighted in the cells from state 2, whereas SimiC shows a different pattern and captures state 0 nicely.…”

Elucidating the fundamental fibrotic processes driving abdominal adhesion formation

“…8a ). EMT is associated with cell proliferation in the setting of neoplasia as well as tissue fibrosis in a variety of organ systems including hepatic and pulmonary fibrosis 23 , 24 . Specific genes of interest in this pathway relating to organ fibrosis include osteopontin ( SPP1 ), periostin ( POSTN ), TIMP1 , cartilage oligomeric matrix protein/thrombospondin-5 ( COMP ), TNC , and N-cadherin ( CDH2 , CD325 ) (Fig.…”

“…4b ). SPP1 is an established JUN target gene and has specifically been associated with JUN -mediated hepatic fibrosis 23 . COMP , a non-collagen ECM protein, and TNC are both upregulated in the context of pulmonary fibrosis, which JUN signaling also mediates 24 , 25 .…”

Altered chromatin landscape and enhancer engagement underlie transcriptional dysregulation in MED12 mutant uterine leiomyomas

“…The dimeric composition of AP-1 determines which AP-1-responsive genes are regulated and whether the resulting AP-1 complex is gene activating or repressive, either directly or through the recruitment of gene-activating or repressive chromatin-modifying complexes 40,41 . Also, AP-1 has been previously implicated in the development of many fibrotic diseases [42][43][44] .…”