Activated Nrf2 Impairs Liver Regeneration in Mice by Activation of Genes Involved in Cell-Cycle Control and Apoptosis
Activated Nrf2 Impairs Liver Regeneration in Mice by Activation of Genes Involved in Cell-Cycle Control and Apoptosis
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DOI：
10.1002/hep.26964
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发表时间：
2014-08-01
期刊：
影响因子：
13.5
通讯作者：
Werner, Sabine
中科院分区：
文献类型：
--
作者：
Koehler, Ulrike A.;Kurinna, Svitlana;Werner, Sabine
核因子red -derived 2， like 2 （Nrf2）转录因子是抗氧化防御系统的关键调控因子，药理激活Nrf2是预防毒素性肝损伤的一种很有前景的策略。然而，Nrf2激活对肝再生（LR）的影响尚未确定。为了解决这个问题，我们培养了在肝细胞中表达组成型活性Nrf2 （caNrf2）突变体的小鼠。转基因基因的表达不影响肝脏稳态。然而，令人惊讶的是，Nrf2激活对ccl4诱导的肝损伤和纤维化没有有益的影响。最重要的是，canrf2转基因小鼠部分肝切除后的LR受损，原因是肝损伤后肝细胞增殖延迟，细胞凋亡增强。在机制上，这涉及到细胞周期蛋白依赖性激酶抑制剂p15和促凋亡蛋白bcl211 （Bim）的上调。通过染色质免疫沉淀，我们发现p15和Bcl2l11基因是Nrf2的直接靶标，Nrf2在肝脏的高增殖条件下被激活。结论：激活Nrf2可延缓再生肝细胞增殖，诱导肝细胞凋亡。当使用Nrf2激活化合物预防肝损伤时，应考虑Nrf2激活对LR的这些负面影响。
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.