1. Activated Nrf2 impairs liver regeneration in mice by activation of genes involved in cell-cycle control and apoptosis.
- Author
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Köhler UA, Kurinna S, Schwitter D, Marti A, Schäfer M, Hellerbrand C, Speicher T, and Werner S
- Subjects
- Animals, Apoptosis Regulatory Proteins metabolism, Bcl-2-Like Protein 11, Carbon Tetrachloride Poisoning genetics, Carbon Tetrachloride Poisoning metabolism, Cell Cycle physiology, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p15 metabolism, Disease Models, Animal, Hepatocytes physiology, Homeostasis physiology, Insulin-Like Growth Factor I metabolism, Liver Cirrhosis genetics, Liver Cirrhosis metabolism, Membrane Proteins metabolism, Mice, Mice, Transgenic, Proto-Oncogene Proteins metabolism, Receptor, Notch1 metabolism, Apoptosis physiology, Chemical and Drug Induced Liver Injury genetics, Chemical and Drug Induced Liver Injury metabolism, Liver Regeneration physiology, NF-E2-Related Factor 2 genetics, NF-E2-Related Factor 2 metabolism
- Abstract
Unlabelled: 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., (© 2014 by the American Association for the Study of Liver Diseases.)
- Published
- 2014
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