Induction of bilirubin clearance by the constitutive androstane receptor (CAR)
Induction of bilirubin clearance by the constitutive androstane receptor (CAR)
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DOI：
10.1073/pnas.0630614100
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发表时间：
2003-04-01
影响因子：
11.1
通讯作者：
Moore, DD
中科院分区：
文献类型：
--
作者：
Huang, WD;Zhang, J;Moore, DD
清除胆红素是肝脏众多重要功能之一。这一过程中的缺陷会导致黄疸，这在新生儿中尤其常见。升高的胆红素水平可通过苯巴比妥治疗而降低。由于核激素受体组成的雄烷受体(CAR)介导了这种异种诱导剂的肝脏效应，我们假设CAR可能是胆红素清除的调节因子。核激素受体CAR的激活增加了胆红素清除途径的五个组成部分中的每一个的肝脏表达。这种诱导在纯合子CAR缺失型小鼠中不存在，但在表达人CAR而不是小鼠CAR的小鼠中观察到。在野生型而不是汽车基因敲除动物中，使用异种诱导剂可显著提高外源性胆红素负荷的清除率。胆红素本身也可以激活CAR，而缺乏CAR的小鼠在清除长期升高的胆红素水平方面存在缺陷。出乎意料的是，在新生小鼠和人类的肝脏中，CAR的表达非常低。我们得出结论，CAR对升高的胆红素水平具有保护性反应，提示CAR活性的功能缺陷可能是新生儿黄疸的原因之一。
Bilirubin clearance is one of the numerous important functions of the liver. Defects in this process result in jaundice, which is particularly common in neonates. Elevated bilirubin levels can be decreased by treatment with phenobarbital. Because the nuclear hormone receptor constitutive androstane receptor (CAR) mediates hepatic effects of this xenobiotic inducer, we hypothesized that CAR could be a regulator of bilirubin clearance. Activation of the nuclear hormone receptor CAR increases hepatic expression of each of five components of the bilirubin-clearance pathway. This induction is absent in homozygous CAR null mice but is observed in mice expressing human CAR instead of mouse CAR. Pretreatment with xenobiotic inducers markedly increases the rate of clearance of an exogenous bilirubin load in wild-type but not CAR knockout animals. Bilirubin itself can also activate CAR, and mice lacking CAR are defective in clearing chronically elevated bilirubin levels. Unexpectedly, CAR expression is very low in livers of neonatal mice and humans. We conclude that CAR directs a protective response to elevated bilirubin levels and suggest that a functional deficit of CAR activity may contribute to neonatal jaundice.