Jnk1 in murine hepatic stellate cells is a crucial mediator of liver fibrogenesis
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2013
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BMJ Publishing Group
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Zhao G, Hatting M, Nevzorova YA, et alJnk1 in murine hepatic stellate cells is a crucial mediator of liver fibrogenesisGut 2014;63:1159-1172
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.
Design: 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.
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Additional material is published online only. To view please visit the journal online (http://dx.doi.org/10.1136/ gutjnl-2013-305507).
Instituciones participantes:
1Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
2Division of Human Nutrition, Nutrition, Metabolism & Genomics Group, Wageningen University, Wageningen, The Netherlands
3Department of Morphology and Molecular Pathology, Liver Research Unit, University of Leuven, Leuven, Belgium
4Institute of Pathology, University Hospital RWTH Aachen, Aachen, Germany
5Howard Hughes Medical Institute and University of Massachusetts Medical School, Worcester, Massachusetts, USA
Correspondence to Dr Francisco Javier Cubero, Department of Internal Medicine III, University
Hospital, RWTH Aachen, Pauwelsstraße, 30, Aachen 52074, Germany;
fcubero@ukaachen.de
GZ and MH contributedequally as first authors.
FJC and CT contributed equallyas senior authors.