Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 285, Issue 7, Pages 5013-5025Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M109.080614
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Funding
- National Institutes of Health [DK080201, NS066417, NS067589, GM084041]
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The retinoic acid receptor-related orphan receptors alpha and gamma (ROR alpha(NR1F1) and ROR gamma(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 ROR alpha ligands, but the physiological significance is unclear. To date, no endogenous ROR alpha ligands have been described. Here, we demonstrate that 7-oxygenated sterols function as high affinity ligands for both ROR alpha and ROR gamma by directly binding to their ligand-binding domains (K-i similar to 20 nM), modulating coactivator binding, and suppressing the transcriptional activity of the receptors. One of the 7-oxygenated sterols, 7 alpha-hydroxycholesterol (7 alpha-OHC), serves as a key intermediate in bile acid metabolism, and we show that 7 alpha-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 7 alpha-OHC functioning as an ROR alpha/gamma ligand. Thus, ROR alpha and ROR gamma are ligand-regulated members of the NR superfamily and may serve as sensors for 7-oxygenated sterols.
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