The transcription factor c-Jun/AP-1 affects non-alcoholic steatohepatitis (NASH) and liver fibrosis in a cell-type specific manner

Question:

The AP-1 transcription factor c-Jun is an essential regulator of hepatocyte survival, liver regeneration and hepatocarcinogenesis. Upstream signalling through c-Jun N-terminal kinases (JNK) was implicated in insulin resistance and steatosis, however, the role of its target c-Jun during NASH remains unknown.

Methods:

c-Jun expression was examined in patient liver biopsies with steatosis and NASH and in mouse models of high fat or methionine- and choline-deficient (MCD) diet. To study the contribution of c-Jun to NASH pathogenesis, the MCD model was applied to mice with a constitutive hepatocyte-specific (c-Jun ^Δli) or inducible c-Jun knock-out in both, parenchymal and non-parenchymal cells (c-Jun ^Δli*), as well as appropriate controls.

Results:

Disease progression from steatosis to NASH correlated with increased expression of c-Jun in both human liver biopsies and control mice. However, steatosis in MCD-fed c-Jun ^Δli mice was strikingly reduced compared to MCD-fed controls. Moreover, hepatocyte proliferation was strongly reduced in the absence of c-Jun, which correlated with increased hepatocellular p21 expression. p21 expression has previously been shown to link regeneration, subsequent ductular reactions and fibrosis in NASH. In keeping with this notion, ductular proliferation of non-parenchymal Sox9 and Osteopontin (Opn) expressing cells was strongly increased in c-Jun ^Δli livers, which also correlated with increased expression of the Opn receptor CD44, NK cell infiltration and liver fibrosis. In contrast, feeding of c-Jun ^Δli* mice (knock-out in hepatocytes and non-parenchymal cells) rather resulted in impaired Opn and CD44 expression and reduced fibrosis. A comparable phenotype characterized by reduced infiltration of Sox9 and Nkp46 cells as well as impaired fibrosis was also observed in Opn ^-/- mice.

Conclusions:

Our results indicate that the functions of hepatic c-Jun expression in NASH may be several-fold. c-Jun expression in hepatocytes regulates proliferation and p21 expression, thereby protecting against the NASH-related ductular reaction and subsequent fibrosis. In contrast, c-Jun expression in non-parenchymal liver cells appears to promote the ductular reaction and fibrosis, likely by regulating OPN expression.