Nrf2 counteracts cholestatic liver injury via stimulation of hepatic defense systems
Nrf2 counteracts cholestatic liver injury via stimulation of hepatic defense systems
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DOI：
10.1016/j.bbrc.2009.08.156
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发表时间：
2009-11-20
影响因子：
3.1
通讯作者：
Yamamoto, Masayuki
中科院分区：
文献类型：
--
作者：
Okada, Kosuke;Shoda, Junichi;Yamamoto, Masayuki
转录因子Nrf2是肝脏诱导解毒酶、抗氧化应激基因和Mrp外排转运蛋白的关键调节因子。我们的目的是研究Nrf2激活是否能抵消与胆汁淤积相关的肝损伤。通过Keap1基因敲低（Keap1-kd）小鼠的胆管结合法（BDL）模型，研究了Nrf2激活在对抗胆汁淤积性肝损伤中的作用，该模型代表了Nrf2在肝脏中的持续激活。Nrf2激活后，Keap1-kd小鼠肝脏中Mrp外排转运体、解毒酶和抗氧化应激基因大量增加。BDL后，Keop1-kd小鼠肝脏实质坏死数量和活性氧含量明显低于W7小鼠。此外，Keap1-kd小鼠血清胆红素水平的升高被减弱。综上所述，结果表明Nrf2的持续激活对胆汁淤积相关的肝损伤具有肝保护作用。(C) 2009爱思唯尔公司版权所有。
The transcription factor Nrf2 is a key regulator for hepatic induction of detoxilying enzymes, antioxidative stress genes and Mrp efflux transporters. We aimed to investigate whether Nrf2 activation counteracts liver injury associated with cholestasis. The role of Nrf2 activation ill Counteracting cholestatic liver injury was studied using a bile duct-ligation (BDL) model of Keap1 gene-knockdown (Keap1-kd) mice that represent the sustained activation of Nrf2 in the liver. Upon Nrf2 activation, Keap1-kd mice showed large increases in Mrp efflux transporters, detoxifying enzymes and antioxidative stress genes in the livers. After BDL, the number of hepatic parenchymal necrosis and the reactive oxygen species content were significantly smaller in the livers of the Keop1-kd mice than in those of the W7 mice. Moreover, the increase in serum bilirubin levels was attenuated in the Keap1-kd mice. In conclusion, the results Suggest a hepatoprotective role of sustained Nrf2 activation against liver injury associated with cholestasis. (C) 2009 Elsevier Inc. All rights reserved.