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Modulation of Retinoic Acid Receptor-related Orphan Receptor α and γ Activity by 7-Oxygenated Sterol Ligands

Year: 2009
Type: article
Abstract: The retinoic acid receptor-related orphan receptors alpha and gamma (RORalpha (NR1F1) and RORgamma (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 RORalpha ligands, but the physiological significance is unclear. To date, no endogenous RORgamma ligands have been described. Here, we demonstrate that 7-oxygenated sterols function as high affinity ligands for both RORalpha and RORgamma by directly binding to their ligand-binding domains (K(i) approximately 20 nM), modulating coactivator binding, and suppressing the transcriptional activity of the receptors. One of the 7-oxygenated sterols, 7alpha-hydroxycholesterol (7alpha-OHC), serves as a key intermediate in bile acid metabolism, and we show that 7alpha-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 7alpha-OHC functioning as an RORalpha/gamma ligand. Thus, RORalpha and RORgamma are ligand-regulated members of the NR superfamily and may serve as sensors for 7-oxygenated sterols.
DOI: 10.1074/jbc.m109.080614
Authors: 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
Language: English
Subfield: Biochemistry
Open Access status: hybrid
Estimated APC paid: $3,430
Funders: National Institutes of Health, National Institute of Mental Health, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, National Center for Research Resources
Awards: Development of RORalpha and RORgamma Ligands for Treatment of Behavioral Disorders, The Comprehensive Center for Chemical Probe Discovery and Optimization at Scripps, Development of a High Throughput Screening Assay for RORgamma, Regulation of REV-ERBalpha and REV-ERBbeta function of HEME, Acquisition of a LTQ/Orbitrap MS to advance the study of protein dynamics, Development and Validation of a REV-ERBalpha HTS Assay, Development of H/D exchange technology for the study of large protein complexes
OpenAlex ID: W2010762097
FWCI: 7.481
Cites: 62
Cited by: 208
Related to: 10