Nrf2 Activation Ameliorates Hepatotoxicity Induced by a Heme Synthesis Inhibitor
Nrf2 Activation Ameliorates Hepatotoxicity Induced by a Heme Synthesis Inhibitor
复制标题
DOI：
10.1093/toxsci/kfy233
复制
发表时间：
2018-09
影响因子：
3.8
通讯作者：
K. Taguchi;S. Masui;T. Itoh;A. Miyajima;Masayuki Yamamoto
中科院分区：
文献类型：
--
作者：
K. Taguchi;S. Masui;T. Itoh;A. Miyajima;Masayuki Yamamoto
转录因子Nrf2通过上调细胞保护基因来保护肝细胞免受各种毒物的伤害。血红素合成抑制剂3，5-二乙氧基-1，4-二氢氯仿(DDC)会导致门静脉周围的肝脏损伤，而不像其他毒物那样会导致小叶中心区域的出血和坏死。为了研究Nrf2是否以及如何保护肝脏免受损伤，我们将DDC喂给Nrf2基因敲除(Nrf2KO)、野生型(WT)、Keap1 Flox/Flox(Keap1-基因敲除；Keap1KD)和肝脏特异性Keap1基因敲除(Keap1-Alb)小鼠，因为这些小鼠的Nrf2蛋白表达水平逐步增加。肝脏特异的Keap1：：Nrf2双基因敲除(Keap1：：Nrf2-Alb)小鼠也被用来检测Nrf2的贡献。DDC喂养2周后，Keap1-Alb小鼠体重完全恢复，而WT和Nrf2KO小鼠则没有。Keap1-Alb小鼠的肝/体重比显著大于WT和Nrf2KO小鼠。肝毒性的两个指标，丙氨酸氨基转移酶和胆红素，在WT小鼠中均升高，但在Keap1-Alb小鼠中在DDC喂养后下调。与WT小鼠相比，DDC诱导的卟啉在Keap1-Alb和Keap1KD小鼠肝脏中的蓄积减少。当以NQO1水平评估时，DDC进一步增强了Keap1-Alb小鼠Nrf2的表达，表明DDC可能具有Keap1独立的激活Nrf2的潜力。在Keap1-Alb小鼠中，Nrf2的基因激活增加了卟啉的胞外排泄，但与我们的预期相反，Nrf2KO小鼠的肝损伤似乎与WT小鼠相似。基于这些观察，我们得出结论，Nrf2的激活对DDC引起的肝脏毒性具有保护作用。
Transcription factor Nrf2 protects hepatocytes against various toxicants by upregulating cytoprotective genes. The heme synthesis inhibitor 3, 5-diethoxycarbonyl-1, 4-dihydrocollidine (DDC) leads to liver injury around the portal vein, unlike other groups of toxicants that cause hemorrhage and necrosis in the centrilobular area. To examine whether and how Nrf2 protects livers from the injury, we fed DDC to Nrf2 knockout (Nrf2KO), wild-type (WT), Keap1flox/flox (Keap1-knockdown; Keap1KD), and liver-specific Keap1 knockout (Keap1-Alb) mice, as these lines of mice exhibit stepwise increases in Nrf2 protein expression levels. Liver-specific Keap1::Nrf2 double-knockout (Keap1::Nrf2-Alb) mice were also exploited to examine the contribution of Nrf2. Two weeks after DDC feeding, Keap1-Alb mice were fully recovered from body weight loss, but the WT and Nrf2KO mice were not. The liver-to-body-weight ratio of Keap1-Alb mice was significantly larger than that of WT and Nrf2KO mice. Two indicators of hepatotoxicity, alanine aminotransferase and bilirubin in plasma, were both elevated in WT mice, but downregulated in Keap1-Alb mice after the DDC-feeding. DDC-induced porphyrin accumulation was reduced in the livers of Keap1-Alb and Keap1KD mice compared with that of WT mice. When assessed by the Nqo1 level, Nrf2 expression was further enhanced by DDC in Keap1-Alb mice, suggesting that DDC may have a Keap1 independent potential to activate Nrf2. Genetic activation of Nrf2 in Keap1-Alb mice increased the extracellular excretion of porphyrins, but contrary to our expectation, hepatic damages in Nrf2KO mice appeared to be similar to that of WT mice. Based on these observations, we conclude that Nrf2 activation protects livers against DDC-elicited hepatotoxicity.