title: Jnk1 in murine hepatic stellate cells is a crucial mediator of liver fibrogenesis.
abstract: 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.
  
  
  METHODS
  Jnk1(f/f) wildtype (WT), Jnk1(-/-) and Jnk1(Δhepa) (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(Δhepa) mice correlating with lower hepatocyte cell death and proliferation. Consequently, parameters of liver fibrosis such as Sirius red staining and collagen IA1 and α-smooth muscle actin expression were downregulated in Jnk1(-/-) compared with WT and Jnk1(Δhepa) 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.
authors.affiliation: Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
authors.forename: Gang
authors.initials: G
authors.lastname: Zhao
authors.affiliation: Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Hatting
authors.affiliation: Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
authors.forename: Yulia A
authors.initials: YA
authors.lastname: Nevzorova
authors.affiliation: Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
authors.forename: Jin
authors.initials: J
authors.lastname: Peng
authors.affiliation: Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
authors.forename: Wei
authors.initials: W
authors.lastname: Hu
authors.affiliation: Division of Human Nutrition, Nutrition, Metabolism & Genomics Group, Wageningen University, Wageningen, The Netherlands.
authors.forename: Mark V
authors.initials: MV
authors.lastname: Boekschoten
authors.affiliation: Department of Morphology and Molecular Pathology, Liver Research Unit, University of Leuven, Leuven, Belgium.
authors.forename: Tania
authors.initials: T
authors.lastname: Roskams
authors.affiliation: Division of Human Nutrition, Nutrition, Metabolism & Genomics Group, Wageningen University, Wageningen, The Netherlands.
authors.forename: Michael
authors.initials: M
authors.lastname: Muller
authors.affiliation: Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Gassler
authors.affiliation: Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Liedtke
authors.affiliation: Howard Hughes Medical Institute and University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Davis
authors.affiliation: Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Cubero
authors.affiliation: Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Trautwein
mesh_terms: D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism; D016026:Bone Marrow Transplantation; D054338:Cell Transdifferentiation; D002908:Chronic Disease; D015536:Down-Regulation; D055166:Hepatic Stellate Cells / Q000201:enzymology*; D022781:Hepatocytes / Q000201:enzymology; D006801:Humans; D008103:Liver Cirrhosis / Q000201:enzymology* / Q000209:etiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D048055:Mitogen-Activated Protein Kinase 8 / Q000172:deficiency / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; D048055:Mitogen-Activated Protein Kinase 8
keywords: CELL SIGNALLING; CHOLESTATIC LIVER DISEASES; DRUG INDUCED HEPATOTOXICITY; FIBROGENESIS; INFLAMMATION