Identification of Oxysterol 7α-Hydroxylase (Cyp7b1) as a Novel Retinoid-Related Orphan Receptor α (RORα) (NR1F1) Target Gene and a Functional Cross-Talk between RORα and Liver X Receptor (NR1H3)
| Autor: | Shikha Bhatia, Taira Wada, Songrong Ren, Haibiao Gong, Martin Angers, Hong Soon Kang, Ewa Ellis, Wen Xie, Anton M. Jetten, Shaheen Khadem, Stephen C. Strom |
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| Rok vydání: | 2007 |
| Předmět: |
Adult
Male Gene isoform medicine.medical_specialty Oxysterol CYP7B1 Receptors Cytoplasmic and Nuclear Mice Inbred Strains Biology Transfection Mice Cytochrome P-450 Enzyme System Genes Reporter Internal medicine medicine Animals Humans Luciferases Promoter Regions Genetic Liver X receptor Receptor Cells Cultured Triglycerides Liver X Receptors Mice Knockout Pharmacology Regulation of gene expression Reporter gene Nuclear Receptor Subfamily 1 Group F Member 1 Fasting Orphan Nuclear Receptors DNA-Binding Proteins Mice Inbred C57BL Cholesterol Endocrinology Gene Expression Regulation Steroid Hydroxylases Hepatocytes Trans-Activators Molecular Medicine Female lipids (amino acids peptides and proteins) |
| Zdroj: | Molecular Pharmacology. 73:891-899 |
| ISSN: | 1521-0111 0026-895X |
| DOI: | 10.1124/mol.107.040741 |
| Popis: | The retinoid-related orphan receptors (RORs) and liver X receptors (LXRs) were postulated to have distinct functions. RORs play a role in tissue development and circadian rhythm, whereas LXRs are sterol sensors that affect lipid homeostasis. In this study, we revealed a novel function of RORalpha (NR1F1) in regulating the oxysterol 7alpha-hydroxylase (Cyp7b1), an enzyme critical for the homeostasis of cholesterol, bile acids, and oxysterols. The expression of Cyp7b1 gene was suppressed in the RORalpha null (RORalpha(sg/sg)) mice, suggesting RORalpha as a positive regulator of Cyp7b1. Promoter analysis established Cyp7b1 as a transcriptional target of RORalpha, and transfection of RORalpha induced the expression of endogenous Cyp7b1 in the liver. Interestingly, Cyp7b1 regulation seemed to be RORalpha-specific, because RORgamma had little effect. Reporter gene analysis showed that the activation of Cyp7b1 gene promoter by RORalpha was suppressed by LXRalpha (NR1H3), whereas RORalpha inhibited both the constitutive and ligand-dependent activities of LXRalpha. The mutual suppression between RORalpha and LXR was supported by the in vivo observation that loss of RORalpha increased the expression of selected LXR target genes, leading to hepatic triglyceride accumulation. Likewise, mice deficient of LXR alpha and beta isoforms showed activation of selected RORalpha target genes. Our results have revealed a novel role for RORalpha and a functional interplay between RORalpha and LXR in regulating endo- and xenobiotic genes, which may have broad implications in metabolic homeostasis. |
| Databáze: | OpenAIRE |
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