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and ROR
in phase I and phase II metabolism
1 Cell Biology Section, National Institutes of Health, Research Triangle Park, North Carolina
4 Microarray Group, Division of Intramural Research, The National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina
2 Stem Cell Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana
3 Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania
Retinoid-related orphan receptors alpha (ROR
) and gamma (ROR
) are both expressed in liver; however, their physiological functions in this tissue have not yet been clearly defined. The ROR
1 and ROR
1 isoforms, but not ROR
4, show an oscillatory pattern of expression during circadian rhythm. To obtain insight into the physiological functions of ROR receptors in liver, we analyzed the gene expression profiles of livers from WT, ROR
-deficient staggerer (sg) mice (ROR
sg/sg), ROR
–/–, and ROR
sg/sgROR
–/– double knockout (DKO) mice by microarray analysis. DKO mice were generated to study functional redundancy between ROR
and ROR
. These analyses demonstrated that ROR
and ROR
affect the expression of a number of genes. ROR
and ROR
are particularly important in the regulation of genes encoding several phase I and phase II metabolic enzymes, including several 3ß-hydroxysteroid dehydrogenases, cytochrome P450 enzymes, and sulfotransferases. In addition, our results indicate that ROR
and ROR
each affect the expression of a specific set of genes but also exhibit functional redundancy. Our study shows that ROR
and ROR
receptors influence the regulation of several metabolic pathways, including those involved in the metabolism of steroids, bile acids, and xenobiotics, suggesting that RORs are important in the control of metabolic homeostasis.
liver; nuclear receptor; metabolism; sulfotransferase; staggerer mice; gene expression analysis; circadian rhythm; retinoid-related orphan receptors
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