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

Dec 20, 2014American journal of physiology. Gastrointestinal and liver physiology

Nrf2 is essential for liver cells to enter the division phase on time during liver regrowth

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Abstract

Nrf2 deficiency led to delayed liver regrowth following 2/3 partial hepatectomy in mice.

Nrf2 null mice showed restored liver mass 7 days post-surgery despite initial delays in regrowth.
The absence of Nrf2 did not reduce the number of hepatocytes entering the cell cycle but delayed their mitosis.
Increased mRNA and protein levels of cyclin A2 were observed in Nrf2 deficient mice during liver replication.
Dysregulation of Wee1, Cdc2, and cyclin B1 was noted in regenerating livers lacking Nrf2.
Nrf2 is associated with timely M phase entry of hepatocytes by regulating cyclin A2 and the Wee1/Cdc2/cyclin B1 pathway.

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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.

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

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