Regulation of drug transporters by the farnesoid X receptor in mice.
Regulation of drug transporters by the farnesoid X receptor in mice.
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DOI：
10.1021/mp0499656
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发表时间：
2004-06
影响因子：
4.9
通讯作者：
Tomoji Maeda;M. Miyata;T. Yotsumoto;Daisuke Kobayashi;T. Nozawa;Keisuke Toyama;F. Gonzalez;Y. Yamazoe;I. Tamai
中科院分区：
文献类型：
--
作者：
Tomoji Maeda;M. Miyata;T. Yotsumoto;Daisuke Kobayashi;T. Nozawa;Keisuke Toyama;F. Gonzalez;Y. Yamazoe;I. Tamai
法尼醇X受体（FXR，NR 1H 4）通过作为细胞内胆汁酸敏感转录因子调节胆汁酸和脂质稳态，导致参与胆汁酸合成和转运的酶和转运蛋白表达改变。在这里，我们定量分析了药物转运蛋白，主要是有机阴离子转运多肽（oatp），在野生型和FXR基因敲除小鼠的表达水平的变化，以评估FXR在其表达和调节胆酸的作用。通过半定量RT-PCR分析在饲料中添加或不添加0.5%胆酸的FXR基因敲除小鼠的肝脏、肾脏、小肠和睾丸中mRNA量的变化。在FXR基因敲除小鼠中，oatp 1、oatp 2、oatp 3和octn 1的mRNA水平在肾脏和睾丸中低于野生型小鼠，而在肝脏和小肠中没有差异。胆酸喂养导致野生型小鼠肝脏中oatp 1和oct 1的表达水平显著降低，oatp 2的表达水平升高。在FXR基因缺失小鼠中，oatp 1和其他转运蛋白在肝脏、肾脏和睾丸中下调，而小肠ASBT、octn 2和pept 1上调。我们的研究结果表明，FXR参与转录调控oatp和其他转运蛋白在组织特异性的方式。此外，胆酸治疗的效果表明FXR以外的调节机制的参与。
The farnesoid X receptor (FXR, NR1H4) regulates bile acid and lipid homeostasis by acting as an intracellular bile acid-sensing transcription factor, resulting in altered expression of enzymes and transporters involved in bile acid synthesis and transport. Here, we quantitatively analyzed the alterations in expression levels of drug transporters, mainly organic anion-transporting polypeptides (oatp), in wild-type and FXR-null mice to evaluate the role of FXR in their expression and regulation by cholic acid. Changes in the mRNA amounts in liver, kidney, small intestine, and testis in FXR-null mice fed with or without a supplement of 0.5% cholic acid in the diet were analyzed by semiquantitative RT-PCR. In FXR-null mice, the mRNA levels of oatp1, oatp2, oatp3, and octn1 were lower than those of wild-type mice in kidney and testis, while there was no difference in liver or small intestine. Cholic acid feeding led to significantly decreased levels of expression of oatp1 and oct1 and an increased level of expression of oatp2 in wild-type mouse liver. In FXR-null mice, oatp1 and other transporters were downregulated in liver, kidney, and testis, whereas small intestine ASBT, octn2, and pept1 were upregulated. Our results suggested that FXR is involved in the transcriptional regulation of oatp and other transporters in a tissue-specific manner. Furthermore, the effect of cholic acid treatment indicates the involvement of regulatory mechanism(s) other than FXR.