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Physiol. Genomics 31: 281-294, 2007. First published July 31, 2007; doi:10.1152/physiolgenomics.00098.2007
1094-8341/07 $8.00
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Received 30 April 2007; accepted in final form 30 July 2007.
Physiological Genomics 31:281-294 (2007)
1094-8341/07 $8.00 © 2007 American Physiological Society

Gene expression profiling reveals a regulatory role for ROR{alpha} and ROR{gamma} in phase I and phase II metabolism

Hong Soon Kang1,*, Martin Angers1,*, Ju Youn Beak1, Xiying Wu2, Jeffrey M. Gimble2, Taira Wada3, Wen Xie3, Jennifer B. Collins4, Sherry F. Grissom4 and Anton M. Jetten1

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{alpha}) and gamma (ROR{gamma}) are both expressed in liver; however, their physiological functions in this tissue have not yet been clearly defined. The ROR{alpha}1 and ROR{gamma}1 isoforms, but not ROR{alpha}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{alpha}-deficient staggerer (sg) mice (ROR{alpha}sg/sg), ROR{gamma}–/–, and ROR{alpha}sg/sgROR{gamma}–/– double knockout (DKO) mice by microarray analysis. DKO mice were generated to study functional redundancy between ROR{alpha} and ROR{gamma}. These analyses demonstrated that ROR{alpha} and ROR{gamma} affect the expression of a number of genes. ROR{alpha} and ROR{gamma} 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{alpha} and ROR{gamma} each affect the expression of a specific set of genes but also exhibit functional redundancy. Our study shows that ROR{alpha} and ROR{gamma} 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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