TY - JOUR
T1 - Modulation of retinoic acid receptor-related orphan receptor α and γ activity by 7-oxygenated sterol ligands
AU - Wang, Yongjun
AU - Kumar, Naresh
AU - Solt, Laura A.
AU - Richardson, Timothy I.
AU - Helvering, Leah M.
AU - Crumbley, Christine
AU - Garcia-Ordonez, Ruben D.
AU - Stayrook, Keith R.
AU - Zhang, Xi
AU - Novick, Scott
AU - Chalmers, Michael J.
AU - Griffin, Patrick R.
AU - Burris, Thomas P.
PY - 2010/2/12
Y1 - 2010/2/12
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M109.080614
DO - 10.1074/jbc.M109.080614
M3 - Article
C2 - 19965867
AN - SCOPUS:77951149298
SN - 0021-9258
VL - 285
SP - 5013
EP - 5025
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 7
ER -