Nrf2 is essential for timely M phase entry of replicating hepatocytes during liver regeneration.
Nrf2 is essential for timely M phase entry of replicating hepatocytes during liver regeneration.
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DOI：
10.1152/ajpgi.00332.2014
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发表时间：
2015-02
期刊：
影响因子：
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通讯作者：
Yuhong Zou;Min Hu;Joonyong Lee;S. M. Nambiar;Veronica Garcia;Q. Bao;J. Chan;G. Dai
中科院分区：
文献类型：
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作者：
Yuhong Zou;Min Hu;Joonyong Lee;S. M. Nambiar;Veronica Garcia;Q. Bao;J. Chan;G. Dai
转录因子核因子红细胞2相关因子2（Nrf 2）调节各种细胞活动，包括氧化还原平衡、解毒、代谢、自噬、增殖和凋亡。几项研究表明，Nrf 2在肝再生过程中调节肝细胞增殖。本研究的目的是研究Nrf 2如何调节再生肝脏中复制肝细胞的细胞周期。对野生型和Nrf 2缺失小鼠进行2/3部分肝切除术（PH），并在多个时间点处死以进行各种分析。Nrf 2缺失小鼠表现出肝脏再生延迟，尽管失去的肝脏质量最终在PH后7天恢复。Nrf 2缺乏不会影响进入细胞周期的肝细胞数量，但确实延迟了肝细胞有丝分裂。从机制上讲，Nrf 2的缺乏导致肝细胞周期蛋白A2的mRNA和蛋白水平增加时，其余的肝细胞复制响应PH。此外，Nrf 2在再生肝脏缺陷引起的Wee 1，Cdc 2，和细胞周期蛋白B1的mRNA和蛋白表达失调，导致Cdc 2活性降低。因此，Nrf 2是复制肝细胞及时进入M期所必需的，通过确保在肝再生过程中对细胞周期蛋白A2和Wee 1/Cdc 2/细胞周期蛋白B1通路的适当调节。
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.