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Physiol. Genomics (July 31, 2007). doi:10.1152/physiolgenomics.00098.2007
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Submitted on April 30, 2007
Accepted on July 30, 2007

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. Gimble3, Taira Wada4, Wen Xie4, Jennifer B Collins5, Sherry F Grissom5, and Anton M. Jetten1*

1 LRB, NIEHS, NIH, Research Triangle Park, North Carolina, United States
2 Pennington Biomedical Research Center, Louisiana State University, United States
3 Pennington Biomedical Research Center, Louisiana State University
4 Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
5 Microarray Group, NIEHS, NIH, Research Triangle Park, North Carolina, United States

* To whom correspondence should be addressed. E-mail: jetten{at}niehs.nih.gov.

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 mice (ROR{alpha}sg/sg), ROR{gamma}-/-, and ROR{alpha}sg/sg ROR{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 3{beta}-hydroxysteroid dehydrogenases (Hsd3b), cytochrome P450 (Cyp) 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.




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