Hepatic Deletion of Janus Kinase 2 Counteracts Oxidative Stress in Mice
Madeleine Themanns1,2, Kristina M Mueller1,2, Sonja M Kessler3
1Ludwig Boltzmann Institute for Cancer Research, 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.
Insights
Blocking JAK2 in the liver prevents fatty liver disease and delays tumor growth by increasing detoxification. This research highlights JAK2
Area of Science:
- Hepatology and Molecular Biology
- Cancer Research
- Endocrinology
Background:
- Genetic deletion of Janus kinase 2 (JAK2) or Signal transducer and activator of transcription 5 (STAT5) in liver impairs growth hormone (GH) signaling, promoting fatty liver disease.
- Hepatic STAT5 deficiency accelerates liver tumor development when GH levels are high.
Purpose of the Study:
- To investigate if the upstream kinase JAK2 has similar functions to STAT5 in liver tumorigenesis.
- To compare the effects of JAK2 deficiency versus STAT5 deficiency in a growth hormone-transgenic mouse model.
Main Methods:
- Mice with hepatocyte-specific JAK2 deletion (JAK2Δhep) were crossed with GH transgenic mice (GHtg).
- JAK2Δhep/GHtg mice were compared to GHtg/STAT5Δhep mice.
- Analysis included steatosis, tumor development, STAT3 activation, oxidative damage, and glutathione S-transferase (GST) expression and activity.
Main Results:
- JAK2 deficiency caused severe steatosis in GHtg mice, similar to STAT5 deficiency.
- Unlike STAT5 deficiency, JAK2 loss significantly delayed liver tumorigenesis.
- JAK2 deficiency prevented STAT3 activation and enhanced hepatic detoxification via increased GST expression and activity, reducing oxidative damage.
Conclusions:
- JAK2 plays a distinct role from STAT5 in liver tumorigenesis, with JAK2 loss offering protection.
- Blocking JAK2 increases hepatic glutathione S-transferases, enhancing detoxification capacity.
- Inhibition of JAK2 protects against oxidative liver damage, suggesting therapeutic potential.
