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Sci Rep. 2016 Oct 7;6:34719. doi: 10.1038/srep34719.

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

Author information

1
Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.
2
Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria.
3
Department of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbrücken, Germany.
4
Center for Biomarker Research in Medicine, Graz, Austria.
5
Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
6
François Rabelais University, CNRS UMR 7292, LNOx team, Tours, France.
7
Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in AUVA Center, Vienna, Austria.
8
Institute of Clinical Pathology, Medical University of Vienna, Vienna, Austria.
9
Institute of Pharmacology, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
10
Molecular Pathology Division, Institute of Pathology, University Hospital of Basel, Basel, Switzerland.
11
Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
12
Unit of Pathology of Laboratory Animals, University of Veterinary Medicine, Vienna, Austria.
13
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, USA.
14
Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
15
Institute of Pathology, Medical University of Graz, Graz, Austria.
16
Medical University of Vienna, Vienna, Austria.

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.

PMID:
27713471
PMCID:
PMC5054456
DOI:
10.1038/srep34719
[Indexed for MEDLINE]
Free PMC Article

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