Hepatocyte-specific deletion of the keap1 gene activates Nrf2 and confers potent resistance against acute drug toxicity
Hepatocyte-specific deletion of the keap1 gene activates Nrf2 and confers potent resistance against acute drug toxicity
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DOI：
10.1016/j.bbrc.2005.10.185
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发表时间：
2006-01-06
影响因子：
3.1
通讯作者：
Yamamoto, M
中科院分区：
文献类型：
--
作者：
Okawa, H;Motohashi, H;Yamamoto, M
Nrf2是许多解毒酶基因的关键调节因子，细胞质蛋白Keap1在静止条件下抑制Nrf2的活性。生殖系Keap1基因的缺失导致了Nrf2的结构性激活，但幼崽在断奶前意外死亡。为了研究Nrf2的结构性激活如何影响成年小鼠的解毒系统，我们产生了携带肝细胞特异性Keap1基因破坏的小鼠。纯合子小鼠是存活的，他们的肝脏没有显示出明显的异常，但Nrf2的核积累增加了。微阵列分析显示，虽然许多解毒酶基因高度表达，但一些典型的Nrf2依赖基因在Keap1缺陷的肝脏中仅略有增加。突变小鼠对有毒剂量的对乙酰氨基酚的抵抗力明显高于对照小鼠。这些结果表明，NRF2的慢性激活使动物对异物具有抵抗力，而不影响肝细胞的形态和生理完整性。(C)2005 Elsevier Inc.保留所有权利。
NrF2 is a key regulator of many detoxifying enzyme genes, and cytoplasmic protein Keap1 represses the Nrf2 activity under quiescent conditions. Germ line deletion of the keap1 gene results in constitutive activation of Nrf2, but the pups unexpectedly died before weaning. To investigate how constitutive activation of Nrf2 influences the detoxification system in adult mice, we generated mice bearing a hepatocyte-specific disruption of the keap1 gene. Homozygous mice were viable and their livers displayed no apparent abnormalities, but nuclear accumulation of Nrf2 is elevated. Microarray analysis revealed that, while many detoxifying enzyme genes are highly expressed, some of the typical Nrf2-dependent genes are only marginally increased in the Keap1-deficient liver. The mutant mice were significantly more resistant to toxic doses of acetaminophen than control animals. These results demonstrate that chronic activation of Nrf2 confers animals with resistance to xenobiotics without affecting the morphological and physiological integrity of hepatocytes. (c) 2005 Elsevier Inc. All rights reserved.