Chemical genomics: Functional analysis of orphan nuclear receptors in the regulation of bile acid metabolism

被引：91

作者：

Willson, TM ^{[1
]}

Jones, SA ^{[1
]}

Moore, JT ^{[1
]}

Kliewer, SA ^{[1
]}

机构：

[1] GlaxoSmithKline, Nucl Receptor Discovery Res, Res Triangle Pk, NC 27709 USA

来源：

MEDICINAL RESEARCH REVIEWS | 2001年 / 21卷 / 06期

关键词：

chemical genomics; orphan nuclear receptors; bile acids; cholestasis;

D O I：

10.1002/med.1023

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Chemical genomics is the name we have given to the analysis of gene function through use of small molecule chemical tools. Orphan nuclear receptors are ideally suited to this technique of functional analysis, since their activity as transcription factors is regulated by small hydrophobic ligands. GW4064 is a potent and selective nonsteroidal ligand for the nuclear bile acid receptor FXR (NR1H4). Using GW4064 as a chemical tool we have identified genes regulated by FXR in the liver, including those involved in bile acid synthesis and transport. We have also discovered that PXR (NR1I2) is a lithocholic acid receptor that controls the biosynthesis and metabolism of bile acids. Together FXR and PXR cooperate to control biliary and urinary bile acid excretion. These functions suggest that potent PXR and FXR ligands may offer a new approach to the treatment of cholestatic liver disease. (C) 2001 John Wiley & Sons, Inc.

引用

页码：513 / 522

页数：10

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