title: Hepatic Deletion of Janus Kinase 2 Counteracts Oxidative Stress in Mice.
abstract: 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 GHtgSTAT5Δhepmice. Similar to GHtgSTAT5Δhepmice, JAK2 deficiency resulted in severe steatosis in the GHtgbackground. 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 GHtgSTAT5Δhepmice, 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.
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.|Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Madeleine
authors.initials: M
authors.lastname: Themanns
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.|Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Kristina M
authors.initials: KM
authors.lastname: Mueller
authors.affiliation: Department of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbrücken, Germany.
authors.forename: Sonja M
authors.initials: SM
authors.lastname: Kessler
authors.affiliation: Center for Biomarker Research in Medicine, Graz, Austria.
authors.forename: Nicole
authors.initials: N
authors.lastname: Golob-Schwarzl
authors.affiliation: Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mohr
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.|Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Doris
authors.initials: D
authors.lastname: Kaltenecker
authors.affiliation: François Rabelais University, CNRS UMR 7292, LNOx team, Tours, France.
authors.forename: Jerome
authors.initials: J
authors.lastname: Bourgeais
authors.affiliation: Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in AUVA Center, Vienna, Austria.
authors.forename: Jamile
authors.initials: J
authors.lastname: Paier-Pourani
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.
authors.forename: Katrin
authors.initials: K
authors.lastname: Friedbichler
authors.affiliation: Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
authors.forename: Doris
authors.initials: D
authors.lastname: Schneller
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.|Institute of Clinical Pathology, Medical University of Vienna, Vienna, Austria.
authors.forename: Michaela
authors.initials: M
authors.lastname: Schlederer
authors.affiliation: Institute of Pharmacology, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: Eva
authors.initials: E
authors.lastname: Zebedin-Brandl
authors.affiliation: Molecular Pathology Division, Institute of Pathology, University Hospital of Basel, Basel, Switzerland.
authors.forename: Luigi M
authors.initials: LM
authors.lastname: Terracciano
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Han
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.|Institute of Clinical Pathology, Medical University of Vienna, Vienna, Austria.|Unit of Pathology of Laboratory Animals, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Lukas
authors.initials: L
authors.lastname: Kenner
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, USA.
authors.forename: Kay-Uwe
authors.initials: KU
authors.lastname: Wagner
authors.affiliation: Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Mikulits
authors.affiliation: Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in AUVA Center, Vienna, Austria.
authors.forename: Andrey V
authors.initials: AV
authors.lastname: Kozlov
authors.affiliation: Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
authors.forename: Markus H
authors.initials: MH
authors.lastname: Heim
authors.affiliation: François Rabelais University, CNRS UMR 7292, LNOx team, Tours, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Gouilleux
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Haybaeck
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.|Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria.|Medical University of Vienna, Vienna, Austria.
authors.forename: Richard
authors.initials: R
authors.lastname: Moriggl
mesh_terms: D000818:Animals; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D017353:Gene Deletion; D005982:Glutathione Transferase / Q000378:metabolism; D019382:Human Growth Hormone / Q000235:genetics*; D053614:Janus Kinase 2 / Q000235:genetics*; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D017382:Reactive Oxygen Species; D019382:Human Growth Hormone; D005982:Glutathione Transferase; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2