Hepatic deletion of Janus Kinase 2 counteracts oxidative stress in mice

Madeleine Themanns, Kristina M. Mueller, Sonja M. Kessler, Nicole Golob-Schwarzl, Thomas Mohr, Doris Kaltenecker, Jerome Bourgeais, Jamile Paier-Pourani, Katrin Friedbichler, Doris Schneller, Michaela Schlederer, Eva Zebedin-Brandl, Luigi M. Terracciano, Xiaonan Han, Lukas Kenner, Kay Uwe Wagner, Wolfgang Mikulits, Andrey V. Kozlov, Markus H. Heim, Fabrice GouilleuxJohannes Haybaeck, Richard Moriggl

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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 (JAK2 δhep) to GH transgenic mice (GH tg) and compared them to GH tg STAT5 δhep mice. Similar to GH tg STAT5 δhep mice, JAK2 deficiency resulted in severe steatosis in the GH tg 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 GH tg STAT5 δhep 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.

Original languageEnglish (US)
Article number34719
JournalScientific reports
Volume6
DOIs
StatePublished - Oct 7 2016

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    Themanns, M., Mueller, K. M., Kessler, S. M., Golob-Schwarzl, N., Mohr, T., Kaltenecker, D., Bourgeais, J., Paier-Pourani, J., Friedbichler, K., Schneller, D., Schlederer, M., Zebedin-Brandl, E., Terracciano, L. M., Han, X., Kenner, L., Wagner, K. U., Mikulits, W., Kozlov, A. V., Heim, M. H., ... Moriggl, R. (2016). Hepatic deletion of Janus Kinase 2 counteracts oxidative stress in mice. Scientific reports, 6, [34719]. https://doi.org/10.1038/srep34719