Modulation of retinoic acid receptor-related orphan receptor α and γ activity by 7-oxygenated sterol ligands

Yongjun Wang, Naresh Kumar, Laura A. Solt, Timothy I. Richardson, Leah M. Helvering, Christine Crumbley, Ruben D. Garcia-Ordonez, Keith R. Stayrook, Xi Zhang, Scott Novick, Michael J. Chalmers, Patrick R. Griffin, Thomas P. Burris

Research output: Contribution to journalArticle

126 Scopus citations

Abstract

The retinoic acid receptor-related orphan receptors α and γ (RORα (NR1F1) and RORγ (NR1F3)) are orphan nuclear receptors and perform critical roles in regulation of development, metabolism, and immune function. Cholesterol and cholesterol sulfate have been suggested to be RORα ligands, but the physiological significance is unclear. To date, no endogenous RORγ ligands have been described. Here, we demonstrate that 7-oxygenated sterols function as high affinity ligands for both RORα and RORγ by directly binding to their ligand-binding domains (Ki ∼20 nM), modulating coactivator binding, and suppressing the transcriptional activity of the receptors. One of the 7-oxygenated sterols, 7α-hydroxycholesterol (7α-OHC), serves as a key intermediate in bile acid metabolism, and we show that 7α-OHC modulates the expression of ROR target genes, including Glc-6-Pase and phosphoenolpyruvate carboxykinase, in an ROR-dependent manner. Furthermore, glucose output from hepatocytes is suppressed by 7α-OHC functioning as an RORα/γ ligand. Thus, RORα and RORγ are ligand-regulated members of the NR superfamily and may serve as sensors for 7-oxygenated sterols.

Original languageEnglish (US)
Pages (from-to)5013-5025
Number of pages13
JournalJournal of Biological Chemistry
Volume285
Issue number7
DOIs
StatePublished - Feb 12 2010

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Wang, Y., Kumar, N., Solt, L. A., Richardson, T. I., Helvering, L. M., Crumbley, C., Garcia-Ordonez, R. D., Stayrook, K. R., Zhang, X., Novick, S., Chalmers, M. J., Griffin, P. R., & Burris, T. P. (2010). Modulation of retinoic acid receptor-related orphan receptor α and γ activity by 7-oxygenated sterol ligands. Journal of Biological Chemistry, 285(7), 5013-5025. https://doi.org/10.1074/jbc.M109.080614