Hepatic Deletion of Janus Kinase 2 Counteracts Oxidative Stress in Mice

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Fatty Liver / genetics
  • Fatty Liver / metabolism
  • Fatty Liver / pathology*
  • Gene Deletion*
  • Glutathione Transferase / metabolism
  • Human Growth Hormone / genetics*
  • Janus Kinase 2 / genetics*
  • Lipid Metabolism
  • Liver / metabolism
  • Liver / pathology*
  • Male
  • Mice
  • Mice, Transgenic
  • Oxidative Stress
  • Reactive Oxygen Species / metabolism
  • Signal Transduction

Substances

  • Reactive Oxygen Species
  • Human Growth Hormone
  • Glutathione Transferase
  • Jak2 protein, mouse
  • Janus Kinase 2