Jnk1 in murine hepatic stellate cells is a crucial mediator of liver fibrogenesis
Program in Molecular Medicine
Animals; Apoptosis; Biomarkers; Bone Marrow Transplantation; Cell Transdifferentiation; Chronic Disease; Down-Regulation; Hepatic Stellate Cells; Hepatocytes; Humans; Liver Cirrhosis; Male; Mice; Mice, Knockout; Mitogen-Activated Protein Kinase 8; Up-Regulation
Biochemistry | Cell Biology | Cellular and Molecular Physiology | Molecular Biology
OBJECTIVE: 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 define the cell type involved in mediating the Jnk1-dependent effect on liver fibrogenesis.
DESIGN: Jnk1(f/f) wildtype (WT), Jnk1(-/-) and Jnk1(Deltahepa) (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), studied their activation in vitro and investigated human diseased liver samples.
RESULTS: Phosphorylated Jnk was expressed in myofibroblasts, epithelial and inflammatory cells during the progression of fibrogenesis in humans and mice. In mice, liver transaminases, alkaline phosphatase, bilirubin and liver histology revealed reduced injury in Jnk1(-/-) compared with WT and Jnk1(Deltahepa) mice correlating with lower hepatocyte cell death and proliferation. Consequently, parameters of liver fibrosis such as Sirius red staining and collagen IA1 and alpha-smooth muscle actin expression were downregulated in Jnk1(-/-) compared with WT and Jnk1(Deltahepa) livers, 4 weeks after CCl4 or BDL. BMT experiments excluded bone marrow-derived cells from having a major impact on the Jnk1-dependent effect on fibrogenesis, while primary HSCs from Jnk1(-/-) livers showed reduced transdifferentiation and extracellular matrix production. Moreover, Jnk1 ablation caused a reduced lifespan and poor differentiation of HSCs into matrix-producing myofibroblasts.
CONCLUSIONS: Jnk1 in HSCs, but not in hepatocytes, significantly contribute to liver fibrosis development, identifying Jnk1 in HSCs as a profibrotic kinase and a promising cell-directed target for liver fibrosis.
CELL SIGNALLING, CHOLESTATIC LIVER DISEASES, DRUG INDUCED HEPATOTOXICITY, FIBROGENESIS, INFLAMMATION
DOI of Published Version
Gut. 2014 Jul;63(7):1159-72. doi: 10.1136/gutjnl-2013-305507. Epub 2013 Sep 13. Link to article on publisher's site
Zhao, Gang; Hatting, Maximilian; Nevzorova, Yulia A.; Peng, Jin; Hu, Wei; Boekschoten, Mark V.; Roskams, Tania; Muller, Michael; Gassler, Nikolaus; Liedtke, Christian; Davis, Roger J.; Cubero, Francisco Javier; and Trautwein, Christian, "Jnk1 in murine hepatic stellate cells is a crucial mediator of liver fibrogenesis" (2014). Davis Lab Publications. 8.