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Impaired liver regeneration in Nrf2 knockout mice: role of ROS‐mediated insulin/IGF‐1 resistance
Author(s) -
Beyer Tobias A,
Xu Weihua,
Teupser Daniel,
auf dem Keller Ulrich,
Bug Philippe,
Hildt Eberhard,
Thiery Joachim,
Kan Yuet Wai,
Werner Sabine
Publication year - 2008
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7601950
Subject(s) - biology , regeneration (biology) , insulin resistance , knockout mouse , liver regeneration , microbiology and biotechnology , insulin , endocrinology , medicine , genetics , gene
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.