Impaired liver regeneration in Nrf2 knockout mice: role of ROS-mediated insulin/IGF-1 resistance.
The liver is frequently challenged by surgery-induced metabolic overload, viruses or toxins, which induce the formation of reactive oxygen species. To determine the effect of oxidative stress on liver regeneration and to identify the underlying signaling pathways, we studied liver repair in mice lacking the Nrf2 transcription factor. In these animals, expression of several cytoprotective enzymes was reduced in hepatocytes, resulting in oxidative stress. After partial hepatectomy, liver regeneration was significantly delayed. Using in vitro and in vivo studies, we identified oxidative stress-mediated insulin/insulin-like growth factor resistance as an underlying mechanism. This deficiency impaired the activation of p38 mitogen-activated kinase, Akt kinase and downstream targets after hepatectomy, resulting in enhanced death and delayed proliferation of hepatocytes. Our results reveal novel roles of Nrf2 in the regulation of growth factor signaling and in tissue repair. In addition, they provide new insight into the mechanisms underlying oxidative stress-induced defects in liver regeneration. These findings may provide the basis for the development of new strategies to improve regeneration in patients with acute or chronic liver damage.
Department of Biology, Institute of Cell Biology, ETH Zurich, Zurich, Switzerland.
Tobias A
TA
Beyer
Weihua
W
Xu
Daniel
D
Teupser
Ulrich
U
auf dem Keller
Philippe
P
Bugnon
Eberhard
E
Hildt
Joachim
J
Thiery
Yuet Wai
YW
Kan
Sabine
S
Werner
D000818:Animals; D002478:Cells, Cultured; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D007328:Insulin / Q000502:physiology*; D007333:Insulin Resistance / Q000235:genetics; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D008115:Liver Regeneration / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D009929:Organ Size / Q000235:genetics; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*
D007328:Insulin; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species; D007334:Insulin-Like Growth Factor I