Loss of Nrf2 in mice evokes a congenital intrahepatic shunt that alters hepatic oxygen and protein expression gradients and toxicity.
Loss of Nrf2 in mice evokes a congenital intrahepatic shunt that alters hepatic oxygen and protein expression gradients and toxicity.
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DOI：
10.1093/toxsci/kfu109
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发表时间：
2014-09
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影响因子：
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通讯作者：
J. Skoko;N. Wakabayashi;K. Noda;Shoko Kimura;K. Tobita;N. Shigemura;Tadayuki Tsujita;Masayuki Yamamoto;T. Kensler
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文献类型：
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作者：
J. Skoko;N. Wakabayashi;K. Noda;Shoko Kimura;K. Tobita;N. Shigemura;Tadayuki Tsujita;Masayuki Yamamoto;T. Kensler
转录因子Nrf2 （Nfe2l2核因子，红细胞2样2）直接调控基因表达，控制药理学和毒理学反应。这些过程也可能受到肝血管结构的影响，肝血管结构通过区隔微环境分配血流以维持机体稳定性。白化C57BL/6J而非ICR Nrf2（-/-）小鼠的肝门静脉血管铸型显示，先天性肝内分流存在于三分之二Nrf2破坏小鼠中。该分流直接连接门静脉和下腔静脉，显示出静脉导管未闭的特征。免疫组织化学显示，与野生型（WT）和未分流的Nrf2（-/-）小鼠相比，肝内分流的Nrf2（-/-）小鼠的肝脏氧和蛋白质表达梯度发生了变化。在没有分流的WT和Nrf2（-/-）小鼠中发现的小叶中心缺氧在有分流的Nrf2（-/-）肝脏中减少。磷酸烯醇丙酮酸羧激酶（Pepck）的肝脏蛋白表达通常局限于门静脉周围区，在Nrf2（-/-）肝内分流小鼠的肝脏中表现出门静脉周围和小叶中心的带状表达。与非分流Nrf2（-/-）肝和非分流Nrf2（-/-）肝相比，分流Nrf2（-/-）肝小叶中心细胞色素P450 2E1 （Cyp2e1）表达减少。研究进一步发现，与WT和Nrf2（-/-）未分流的小鼠相比，Nrf2（-/-）肝内分流在250 mg/kg对乙酰氨基酚灌胃6小时后，可降低对乙酰氨基酚的肝毒性。肝内分流的存在通过血流、肝氧合和蛋白质表达的变化影响Nrf2（-/-）小鼠的几种生理和病理生理特性，其程度超出了Nrf2靶基因典型转激活的丧失。
The transcription factor Nrf2 (Nfe2l2 nuclear factor, erythroid 2-like 2) regulates gene expression directly, controlling pharmacological and toxicological responses. These processes may also be influenced by the structure of the hepatic vasculature, which distributes blood flow through compartmentalized microenvironments to maintain organismal stability. Castings of the hepatic portal vasculature of albino C57BL/6J but not ICR Nrf2(-/-) mice revealed a congenital intrahepatic shunt that was present in two thirds of Nrf2-disrupted mice. This shunt directly connected the portal vein to the inferior vena cava and displayed characteristics of a patent ductus venosus. Immunohistochemistry revealed that Nrf2(-/-) mice with an intrahepatic shunt manifest changes to hepatic oxygen and protein expression gradients when compared with wild-type (WT) and non-shunted Nrf2(-/-) mice. Centrilobular hypoxia found in WT and Nrf2(-/-) mice without shunts was reduced in Nrf2(-/-) livers with a shunt. Hepatic protein expression of phosphoenolpyruvate carboxykinase (Pepck), normally confined to the periportal zone, exhibited both periportal and centrilobular zonal expression in livers from Nrf2(-/-) mice with an intrahepatic shunt. Centrilobular expression of Cytochrome P450 2E1 (Cyp2e1) was diminished in shunted Nrf2(-/-) livers compared with WT and Nrf2(-/-) livers without shunts. The intrahepatic shunt in Nrf2(-/-) mice was further found to diminish acetaminophen hepatoxicity compared with WT and Nrf2(-/-) non-shunted mice following a 6 h challenge with 250 mg/kg acetaminophen. The presence of an intrahepatic shunt influences several physiological and pathophysiological properties of Nrf2(-/-) mice through changes in blood flow, hepatic oxygenation, and protein expression that extent beyond loss of canonical transactivation of Nrf2 target genes.