Hepatic Deletion of Janus Kinase 2 Counteracts Oxidative Stress in Mice
| Autor: | Xiaonan Han, Nicole Golob-Schwarzl, Richard Moriggl, Wolfgang Mikulits, Markus H. Heim, Sonja M. Kessler, Doris Kaltenecker, Kristina M. Mueller, Katrin Friedbichler, Johannes Haybaeck, Jamile Paier-Pourani, Eva Zebedin-Brandl, Doris Schneller, Thomas Mohr, Lukas Kenner, Kay Uwe Wagner, Andrey V. Kozlov, Michaela Schlederer, Fabrice Gouilleux, Luigi Terracciano, Madeleine Themanns, Jérôme Bourgeais |
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| Přispěvatelé: | Medical University of Graz, Medical University of Vienna, Inst Canc Res, Dept Med, Medizinische Universität Wien = Medical University of Vienna, Génétique, immunothérapie, chimie et cancer (GICC), UMR 7292 CNRS [2012-2017] (GICC UMR 7292 CNRS), Université de Tours-Centre National de la Recherche Scientifique (CNRS), Institut des Matériaux, de Microélectronique et des Nanosciences de Provence (IM2NP), Université de Toulon (UTLN)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), BBVA Foundation - Cancer Cell Biology Programme, Ludwig Boltzman Institute for Clinical and Experimental Traumatology, Lorenz Boehler Hospital, University Hospital Basel [Basel], Ludwig Boltzmann Institute for Cancer Research [Vienna, Austria], Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Université de Toulon (UTLN)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male medicine.medical_specialty [SDV]Life Sciences [q-bio] Mice Transgenic [SDV.CAN]Life Sciences [q-bio]/Cancer [SDV.BC]Life Sciences [q-bio]/Cellular Biology medicine.disease_cause Article 03 medical and health sciences chemistry.chemical_compound Mice Internal medicine hemic and lymphatic diseases medicine Animals [SDV.BBM]Life Sciences [q-bio]/Biochemistry Molecular Biology STAT3 ComputingMilieux_MISCELLANEOUS Glutathione Transferase chemistry.chemical_classification Reactive oxygen species Gene knockdown Multidisciplinary Janus kinase 2 biology Human Growth Hormone Fatty liver food and beverages Glutathione Janus Kinase 2 medicine.disease Lipid Metabolism Fatty Liver Oxidative Stress 030104 developmental biology Endocrinology chemistry Liver biology.protein Cancer research Steatosis Reactive Oxygen Species Oxidative stress Gene Deletion Signal Transduction |
| Zdroj: | Scientific Reports Scientific Reports, Nature Publishing Group, 2016, 6 (1), ⟨10.1038/srep34719⟩ Scientific Reports, 2016, 6 (1), ⟨10.1038/srep34719⟩ |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/srep34719⟩ |
| Popis: | Genetic deletion of the tyrosine kinase JAK2 or the downstream transcription factor STAT5 in liver impairs growth hormone (GH) signalling and thereby promotes fatty liver disease. Hepatic STAT5 deficiency accelerates liver tumourigenesis in presence of high GH levels. To determine whether the upstream kinase JAK2 exerts similar functions, we crossed mice harbouring a hepatocyte-specific deletion of JAK2 (JAK2Δhep) to GH transgenic mice (GHtg) and compared them to GHtgSTAT5Δhep mice. Similar to GHtgSTAT5Δhep mice, JAK2 deficiency resulted in severe steatosis in the GHtg background. However, in contrast to STAT5 deficiency, loss of JAK2 significantly delayed liver tumourigenesis. This was attributed to: (i) activation of STAT3 in STAT5-deficient mice, which was prevented by JAK2 deficiency and (ii) increased detoxification capacity of JAK2-deficient livers, which diminished oxidative damage as compared to GHtgSTAT5Δhep mice, despite equally severe steatosis and reactive oxygen species (ROS) production. The reduced oxidative damage in JAK2-deficient livers was linked to increased expression and activity of glutathione S-transferases (GSTs). Consistent with genetic deletion of Jak2, pharmacological inhibition and siRNA-mediated knockdown of Jak2 led to significant upregulation of Gst isoforms and to reduced hepatic oxidative DNA damage. Therefore, blocking JAK2 function increases detoxifying GSTs in hepatocytes and protects against oxidative liver damage. |
| Databáze: | OpenAIRE |
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