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Type of publication: Journal Article
Type of document: Full Paper

Year: 2016

Authors: Themanns, M; Mueller, KM; Kessler, SM; Golob-Schwarzl, N; Mohr, T; Kaltenecker, D; Bourgeais, J; Paier-Pourani, J; Friedbichler, K; Schneller, D; Schlederer, M; Zebedin-Brandl, E; Terracciano, LM; Han, X; Kenner, L; Wagner, KU; Mikulits, W; Kozlov, AV; Heim, MH; Gouilleux, F; Haybaeck, J; Moriggl, R

Title: Hepatic Deletion of Janus Kinase 2 Counteracts Oxidative Stress in Mice.

Source: Sci Rep. 2016; 6:34719



Authors Vetmeduni Vienna:

Kenner Lukas
Moriggl Richard
Müller Kristina
Themanns Madeleine

Vetmed Research Units
Institute of Pathology, Pathology of Laboratory Animals
Institute of Animal Breeding and Genetics, Unit for Functional Cancer Genomics


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 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.

Keywords Pubmed: Animals
Fatty Livergeneticsmetabolismpathology
Gene Deletion
Glutathione Transferasemetabolism
Human Growth Hormonegenetics
Janus Kinase 2genetics
Lipid Metabolism
Livermetabolismpathology
Male
Mice
Mice, Transgenic
Oxidative Stress
Reactive Oxygen Speciesmetabolism
Signal Transduction

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