Gene expression profiling reveals a regulatory role for ROR alpha and ROR gamma in phase I and phase II metabolism.
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 alpha1 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/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 3beta-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.
Cell Biology Section, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
Hong Soon
HS
Kang
Martin
M
Angers
Ju Youn
JY
Beak
Xiying
X
Wu
Jeffrey M
JM
Gimble
Taira
T
Wada
Wen
W
Xie
Jennifer B
JB
Collins
Sherry F
SF
Grissom
Anton M
AM
Jetten
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D002478:Cells, Cultured / Q000378:metabolism; D002940:Circadian Rhythm / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D022781:Hepatocytes / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics; D008099:Liver / Q000378:metabolism; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008818:Mice, Neurologic Mutants; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018168:Receptors, Retinoic Acid / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011988:Receptors, Thyroid Hormone / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013256:Steroids / Q000378:metabolism; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D015262:Xenobiotics / Q000378:metabolism
D001647:Bile Acids and Salts; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D011993:Recombinant Fusion Proteins; C539901:Rorc protein, mouse; D013256:Steroids; D015534:Trans-Activators; D015262:Xenobiotics; D003577:Cytochrome P-450 Enzyme System