Okada Kosuke, Shoda Junichi, Taguchi Keiko, Maher Jonathan M, Ishizaki Kaoru, Inoue Yoshimi, Ohtsuki Makio, Goto Nobuharu, Sugimoto Hirokazu, Utsunomiya Hirotoshi, Oda Koji, Warabi Eiji, Ishii Tetsuro, Yamamoto Masayuki
Department of Molecular and Cellular Physiology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
Biochem Biophys Res Commun. 2009 Nov 20;389(3):431-6. doi: 10.1016/j.bbrc.2009.08.156. Epub 2009 Sep 2.
The transcription factor Nrf2 is a key regulator for hepatic induction of detoxifying 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 in 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 Keap1-kd mice than in those of the WT 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.
转录因子Nrf2是肝脏中诱导解毒酶、抗氧化应激基因和Mrp外排转运蛋白的关键调节因子。我们旨在研究Nrf2激活是否能对抗与胆汁淤积相关的肝损伤。使用Keap1基因敲除（Keap1-kd）小鼠的胆管结扎（BDL）模型研究了Nrf2激活在对抗胆汁淤积性肝损伤中的作用，该模型代表肝脏中Nrf2的持续激活。Nrf2激活后，Keap1-kd小鼠肝脏中的Mrp外排转运蛋白、解毒酶和抗氧化应激基因大幅增加。BDL后，Keap1-kd小鼠肝脏中的肝实质坏死数量和活性氧含量明显低于野生型小鼠。此外，Keap1-kd小鼠血清胆红素水平的升高有所减轻。总之，结果表明Nrf2持续激活对与胆汁淤积相关的肝损伤具有肝保护作用。
