Hepatic Stellate Cells-derived JNK1 is a crucial mediator

Background and Aim: Hepatic fibrosis is a wound-healing response to chronic liver injury, which frequently results 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. Methods: Wild-type (WT), Jnk1–/– and Jnk1Δhepa (hepatocyte-specific deletion of JNK1) mice were subjected to (i) bile duct ligation (BDL) and (ii) CCl4- induced liver fibrosis. Additionally, we performed bone marrow transplantations (BMT), isolated primary hepatic stellate cells (HSCs) and studied their activation in vitro. Results: Serum markers of liver damage (liver transaminases, alkaline phosphatase and bilirubin) and liver histology revealed reduced injury in Jnk1–/– compared to WT and Jnk1Δhepa mice. Hepatocyte cell death and proliferation was reduced in Jnk1–/– compared to WT and Jnk1Δhepa livers. Parameters of liver fibrosis such as Sirius Red staining as well as Collagen IA1 and αSMA expression were down-regulated in Jnk1–/– compared to WT and Jnk1Δhepa livers, 4 weeks after CCl4 or 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 Jnk1Δhepa-derived HSCs. Conclusion: Jnk1 in HSCs plays a crucial role in hepatic fibrogenesis and thus is a promising target for cell-directed treatment options of liver fibrosis.