Potential conflict of interest: Nothing to report.
Activated Nrf2 impairs liver regeneration in mice by activation of genes involved in cell-cycle control and apoptosis
Article first published online: 18 JUN 2014
© 2014 by the American Association for the Study of Liver Diseases
Volume 60, Issue 2, pages 670–678, August 2014
How to Cite
Köhler, U. A., Kurinna, S., Schwitter, D., Marti, A., Schäfer, M., Hellerbrand, C., Speicher, T. and Werner, S. (2014), Activated Nrf2 impairs liver regeneration in mice by activation of genes involved in cell-cycle control and apoptosis. Hepatology, 60: 670–678. doi: 10.1002/hep.26964
This work was supported by ETH Zurich (TH grant no. 0-23123-08; to S.W.), the Swiss National Science Foundation (grant 310030-142884; to S.W.), and Boehringer Ingelheim Fonds (predoctoral fellowship to U.A.K.).
See Editorial on Page 461
- Issue published online: 22 JUL 2014
- Article first published online: 18 JUN 2014
- Accepted manuscript online: 6 DEC 2013 02:19AM EST
- Manuscript Accepted: 4 DEC 2013
- Manuscript Received: 30 SEP 2013
The nuclear factor erythroid-derived 2, like 2 (Nrf2) transcription factor is a key regulator of the antioxidant defense system, and pharmacological activation of Nrf2 is a promising strategy for prevention of toxin-induced liver damage. However, the consequences of Nrf2 activation on liver regeneration (LR) have not been determined. To address this question, we generated mice expressing a constitutively active Nrf2 (caNrf2) mutant in hepatocytes. Expression of the transgene did not affect liver homeostasis. Surprisingly, however, there was no beneficial effect of Nrf2 activation on CCl4-induced liver injury and fibrosis. Most important, LR after partial hepatectomy was impaired in caNrf2-transgenic mice as a result of delayed hepatocyte proliferation and enhanced apoptosis of these cells after liver injury. Mechanistically, this involved up-regulation of the cyclin-dependent kinase inhibitor p15 and the proapoptotic protein Bcl2l11 (Bim). Using chromatin immunoprecipitation, we show that the p15 and Bcl2l11 genes are direct targets of Nrf2, which are activated under hyperproliferative conditions in the liver. Conclusion: Activated Nrf2 delays proliferation and induces apoptosis of hepatocytes in the regenerating liver. These negative effects of Nrf2 activation on LR should be considered when Nrf2-activating compounds are used for prevention of liver damage. (Hepatology 2014;60:670–678)