Nrf2 is essential for timely M phase entry of replicating hepatocytes during liver regeneration

The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) regulates various cellular activities, including redox balance, detoxification, metabolism, autophagy, proliferation, and apoptosis. Several studies have demonstrated that Nrf2 regulates hepatocyte proliferation during liver...

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Published in:American journal of physiology: Gastrointestinal and liver physiology 2015-02, Vol.308 (4), p.G262-G268
Main Authors: Zou, Yuhong, Hu, Min, Lee, Joonyong, Nambiar, Shashank Manohar, Garcia, Veronica, Bao, Qi, Chan, Jefferson Y, Dai, Guoli
Format: Article
Language:English
Subjects:
Animals
CDC2 Protein Kinase - genetics
CDC2 Protein Kinase - metabolism
Cell Cycle Proteins - genetics
Cell Cycle Proteins - metabolism
Cell Division
Cellular biology
Cyclin A2 - genetics
Cyclin A2 - metabolism
Cyclin B1 - genetics
Cyclin B1 - metabolism
Erythrocytes
Gene Expression Regulation
Hepatectomy
Hepatocytes - metabolism
Hepatocytes - pathology
Hepatology
Kinetics
Liver
Liver - metabolism
Liver - pathology
Liver - surgery
Liver and Biliary Tract
Liver Regeneration
Male
Mice, 129 Strain
Mice, Inbred C57BL
Mice, Knockout
Mitosis
NF-E2-Related Factor 2 - deficiency
NF-E2-Related Factor 2 - genetics
NF-E2-Related Factor 2 - metabolism
Nuclear Proteins - genetics
Nuclear Proteins - metabolism
Physiology
Protein-Tyrosine Kinases - genetics
Protein-Tyrosine Kinases - metabolism
RNA, Messenger - metabolism
RNA-protein interactions
Rodents
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Summary:The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) regulates various cellular activities, including redox balance, detoxification, metabolism, autophagy, proliferation, and apoptosis. Several studies have demonstrated that Nrf2 regulates hepatocyte proliferation during liver regeneration. The aim of this study was to investigate how Nrf2 modulates the cell cycle of replicating hepatocytes in regenerating livers. Wild-type and Nrf2 null mice were subjected to 2/3 partial hepatectomy (PH) and killed at multiple time points for various analyses. Nrf2 null mice exhibited delayed liver regrowth, although the lost liver mass was eventually restored 7 days after PH. Nrf2 deficiency did not affect the number of hepatocytes entering the cell cycle but did delay hepatocyte mitosis. Mechanistically, the lack of Nrf2 resulted in increased mRNA and protein levels of hepatic cyclin A2 when the remaining hepatocytes were replicating in response to PH. Moreover, Nrf2 deficiency in regenerating livers caused dysregulation of Wee1, Cdc2, and cyclin B1 mRNA and protein expression, leading to decreased Cdc2 activity. Thus, Nrf2 is required for timely M phase entry of replicating hepatocytes by ensuring proper regulation of cyclin A2 and the Wee1/Cdc2/cyclin B1 pathway during liver regeneration.
ISSN:0193-1857
1522-1547
DOI:10.1152/ajpgi.00332.2014