Absence of JNK activity in hepatocytes exacerbates liver injury and fibrosis during chronic cholestasis in mice

Zeitschrift für Gastroenterologie

Abstract

Background: The c-Jun NH2-terminal kinase (JNK) activation is required for cholestatic liver injury-induced fibrogenesis. Global JNK1 or JNK2 functions have been thoroughly addressed. Moreover, we showed that JNK1 function in hepatic stellate cells (HSCs), but not in hepatocytes mediates transactivation of HSCs during murine liver fibrosis. Here, we tested the hypothesis that JNK1 and JNK2 together in hepatocytes work to confer protection during cholestatic liver injury-induced liver fibrosis. Methods: The relevance of JNK in human and experimental cholestatic liver disease was tested. Additionally, Jnk1/2 f/f (WT) and Jnk1/2 Δhepa (hepatocyte-specific deletion of JNK1 and JNK2) mice were subjected to bile duct ligation (BDL) for 28 days. Mdr2 knockout mice were also used. Moreover, microarray analysis was performed. Results: Activation of JNK is characteristic in human (primary biliary cholangitis, PBC and primary sclerosing cholangitis, PSC) and in murine cholestasis (Mdr2 -/- and BDL). Serum markers of hepatic damage – liver transaminases – and liver histology revealed increased cell death, hepatic fibrogenesis, oxidative stress and inflammation in Jnk1/2 Δhepa mice compared to WT, 28-days after BDL. Furthermore, microarray analysis indicated protection of the mucosal epithelium since Mucin and Trefoil family members were strongly upregulated in absence of hepatocytic JNK1/2. Conclusion: Combined function of JNK1 and JNK2 in hepatocytes protects against the development of cholestatic liver disease.

Authors 6

1. Mohamed Ramadan Mohamed Aachen Department of Internal Medicine III

   RWTH Aachen University · Universitätsklinikum Aachen · National Research Centre

   Affiliation as printed

   National Research Centre, Department of Therapeutic Chemistry, Cairo, Egypt

   University Hospital RWTH Aachen, Department of Internal Medicine III, Aachen, Germany

2. FJ Cubero Aachen Department of Internal Medicine III

   RWTH Aachen University · Universitätsklinikum Aachen · Universidad Complutense de Madrid · Research Institute Hospital 12 de Octubre

   Affiliation as printed

   12 de Octubre Health Research Institute (imas12), Madrid, Spain

   Complutense University School of Medicine, Department of Immunology, Ophthalmology & ENT, Madrid, Spain

   University Hospital RWTH Aachen, Department of Internal Medicine III, Aachen, Germany

3. Johannes Haybäck

   Medical University of Graz

   Affiliation as printed

   Institute of Pathology, Medical University of Graz, Diagnostic and Research Center for Molecular BioMedicine, Graz, Austria

4. M.V. Boekschoten

   Wageningen University & Research

   Affiliation as printed

   Wageningen University, Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen, Netherlands

5. RJ Davis

   Howard Hughes Medical Institute · University of Massachusetts Chan Medical School

   Affiliation as printed

   Howard Hughes Medical Institute and University of Massachusetts Medical School, Massachusetts, United States

6. Christian Trautwein Aachen Department of Internal Medicine III

   RWTH Aachen University · Universitätsklinikum Aachen

   Affiliation as printed

   University Hospital RWTH Aachen, Department of Internal Medicine III, Aachen, Germany