PXR and the regulation of apoA1 and HDL-cholesterol in rodents
PXR and the regulation of apoA1 and HDL-cholesterol in rodents
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DOI：
10.1016/j.phrs.2004.03.005
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发表时间：
2004-09-01
影响因子：
9.3
通讯作者：
Sambucetti, L
中科院分区：
文献类型：
--
作者：
Bachmann, K;Patel, H;Sambucetti, L
孤儿核受体（ONR）已经涉及脂质的调节。一些前瞻性或流行病学的临床研究指出，肝纤维化酶的调节与HDL-胆固醇（HDL-C）和/或载脂蛋白A1（apoA 1）之间存在联系。用一系列CYP 3A的咪唑诱导剂治疗大鼠，产生了体外CYP 3A活性（以红霉素脱甲基酶活性测量）与血浆HDL-C和肝脏apoA 1 mRNA之间的相关性。同样，体内CYP 3A活性（以乙琥胺清除率测量）与血浆HDL-C和肝脏apoA 1 mRNA之间也建立了相关性。用PXR激动剂治疗野生型（WT）小鼠引起血清HDL-C和血清apoA 1水平升高。另一方面，用相同的PXR激动剂治疗PXR敲除小鼠（PXR-KO）未能引起血清HDL-C或血清apoA 1水平的升高。将大鼠中已知为活性CYP 3A诱导剂的三种咪唑类化合物的结构与人PXR药效团叠加，证明了部分拟合，并预测了人体中弱-中度hPXR诱导剂的典型EC 50值。这些咪唑类药物已被证明可增加大鼠和小鼠的apoA 1和HDL-C。综上所述，这些数据表明，PXR在啮齿类动物apoA 1和HDL-C的调节中起着重要作用。(C)2004爱思唯尔有限公司保留所有权利。
Orphan nuclear receptors (ONRs) have been implicated in the regulation of lipids. Several clinical studies conducted either prospectively or epidemiologically have pointed to a link between the regulation of hepatic CYP enzymes and HDL-cholesterol (HDL-C) and/or apolipoprotein A1 (apoA1). The treatment of rats with a series of imidazole inducers of CYP3A yielded correlations between in vitro CYP3A activity measured as erythromycin demethylase activity and plasma HDL-C and hepatic apoA1 mRNA. Similarly, a correlation was established between in vivo CYP3A activity, measured as ethosuximide clearance, and plasma HDL-C and hepatic apoA1 mRNA. The treatment of wild-type (WT) mice with PXR agonists elicited increases in serum HDL-C and serum apoA1 levels. On the other hand, the treatment of PXR-knockout mice (PXR-KOs) with the same PXR agonists failed to elicit increases in either serum HDL-C or serum apoA1 levels. Superposition of the structures of three imidazoles known to be active CYP3A inducers in rats with the human PXR pharmacophore demonstrated a partial fit and predicted EC50 values typical of weak-moderate hPXR inducers in humans. These imidazoles have been shown to increase apoA1 and HDL-C in rats and mice. Taken together, these data suggest that PXR plays an important role in the regulation of apoA1 and HDL-C in rodents. (C) 2004 Elsevier Ltd. All rights reserved.