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

Timothy M. Willson, Stacey A. Jones, John T. Moore, Steven A. Kliewer

Research output: Contribution to journalArticle

98 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)513-522
Number of pages10
JournalMedicinal Research Reviews
Volume21
Issue number6
DOIs
StatePublished - 2001

Keywords

  • Bile acids
  • Chemical genomics
  • Cholestasis
  • Orphan nuclear receptors

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology
  • Drug Discovery

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