Jnk1 in murine hepatic stellate cells is a crucial mediator of liver fibrogenesis
Authors
Zhao, GangHatting, 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
Trautwein, Christian
UMass Chan Affiliations
Program in Molecular MedicineDocument Type
Journal ArticlePublication Date
2014-07-01Keywords
AnimalsApoptosis
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
CELL SIGNALLING
CHOLESTATIC LIVER DISEASES
DRUG INDUCED HEPATOTOXICITY
FIBROGENESIS
INFLAMMATION
Biochemistry
Cell Biology
Cellular and Molecular Physiology
Molecular Biology
Metadata
Show full item recordAbstract
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.Source
Gut. 2014 Jul;63(7):1159-72. doi: 10.1136/gutjnl-2013-305507. Epub 2013 Sep 13. Link to article on publisher's siteDOI
10.1136/gutjnl-2013-305507Permanent Link to this Item
http://hdl.handle.net/20.500.14038/28354PubMed ID
24037431Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1136/gutjnl-2013-305507