Jnk1 in murine hepatic stellate cells is a crucial mediator of liver fibrogenesis

Hepatic fibrosis is a wound-healing response to chronic liver injury, which may result in cirrhosis and liver failure. The c-Jun N-terminal kinase-1 (JNK1) gene has been shown to be involved in liver fibrosis. Here, we aimed to investigate the molecular mechanism and identify the cell-type involved in mediating the JNK1-dependent effect on liver fibrogenesis Wild-type (WT), JNK1/ and JNK1hepa (hepatocyte-specific deletion of JNK1) mice were subjected to bile duct ligation (BDL). Additionally, we performed bone marrow transplantations (BMT), isolated primary hepatic stellate cells (HSCs) and studied their activation in vitro. Serum markers of liver damage (liver transaminases, alkaline phosphatase and bilirubin) and liver histology revealed reduced injury in JNK1/ compared to WT and JNK1hepa mice. Hepatocyte cell death and proliferation was reduced in JNK1/ compared to WT and JNK1hepa. Parameters of liver fibrosis such as Sirius Red staining as well as Collagen IA1 and SMA expression were down-regulated in JNK1/ compared to WT and JNK1hepa livers, 4 weeks after BDL. To delineate the essential cell-type, we performed BMT of WT and JNK1-/- into JNK1-/- and WT mice, respectively. BMT experiments excluded bone marrow derived cells from having a major impact on the JNK1-dependent effect on fibrogenesis. Hence, we investigated primary HSCs from JNK1/ livers showing reduced transdifferentiation compared with WT and JNK1hepa-derived HSCs. We conclude that JNK1 in HSCs plays a crucial role in hepatic fibrogenesis and thus represents a promising target for cell-directed treatment options for liver fibrosis.

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Zhao G, Hatting M, Nevzorova YA, Peng J, Hu W, Boekschoten MV, Roskams T, Muller M, Gassler N, Liedtke C, Davis RJ, Cubero FJ, Trautwein C