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Gene expression profiling reveals a regulatory role for RORalpha and RORgamma in Phase I and Phase II Metabolism

ABSTRACT: Retinoid-related orphan receptors RORalpha and RORgamma are both expressed in liver; however, their physiological functions have not yet been clearly defined. RORalpha1 and RORgamma1, but not RORalpha4, 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, RORalpha-deficient staggerer mice (RORalphasg/sg), RORgamma-/-, and RORalpha sg/sgRORgamma-/- double knockout (DKO) mice by microarray analysis. DKO mice were generated to study functional redundancy between RORalpha and RORgamma. These analyses demonstrated that RORalpha and RORgamma affect the expression of a number of genes. RORalpha and RORalpha are particularly important in the regulation of genes encoding several Phase I and Phase II metabolic enzymes, including several 3beta-hydroxysteroid dehydrogenases (Hsd3b), the cytochrome P450 (Cyp) enzymes Cyp7b1, Cyp4a14, and Cyp8b1, and the sulfotransferases Sult1e1 and Sult2a1. Our data show that RORalpha and RORgamma can influence gene expression positively as well as negatively. In addition, our results indicate that RORalpha and RORgamma each affect the expression of a specific set of genes but also exhibit functional redundancy. Our study shows that RORalpha and RORgamma 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. Keywords: knockout comparison

ORGANISM(S): Mus musculus

PROVIDER: GSE7564 | GEO | 2007/08/24

SECONDARY ACCESSION(S): PRJNA100331

REPOSITORIES: GEO

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Transcription profiling of mouse liver from wild type (WT), RORalphasg/sg, RORgamma-/-, and double knockout animals reveals a regulatory role for RORalpha and RORgamma in Phase I and Phase II Metabolism

Project description:Retinoid-related orphan receptors RORalpha and RORgamma are both expressed in liver; however, their physiological functions have not yet been clearly defined. RORalpha1 and RORgamma1, but not RORalpha4, 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, RORalpha-deficient staggerer mice (RORalphasg/sg), RORgamma-/-, and RORalpha sg/sgRORgamma-/- double knockout (DKO) mice by microarray analysis. DKO mice were generated to study functional redundancy between RORalpha and RORgamma. These analyses demonstrated that RORalpha and RORgamma affect the expression of a number of genes. RORalpha and RORalpha are particularly important in the regulation of genes encoding several Phase I and Phase II metabolic enzymes, including several 3beta-hydroxysteroid dehydrogenases (Hsd3b), the cytochrome P450 (Cyp) enzymes Cyp7b1, Cyp4a14, and Cyp8b1, and the sulfotransferases Sult1e1 and Sult2a1. Our data show that RORalpha and RORgamma can influence gene expression positively as well as negatively. In addition, our results indicate that RORalpha and RORgamma each affect the expression of a specific set of genes but also exhibit functional redundancy. Our study shows that RORalpha and RORgamma 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. Experiment Overall Design: We generated RORalpha and RORgamma double knockout (DKO) mice and compared the gene expression profiles of livers from wild type (WT), RORalphasg/sg, RORgamma-/-, and DKO mice by microarray analysis

2008-06-15 | E-GEOD-7564 | biostudies-arrayexpress

Nuclear receptor, RORa plays a critical role in obesity-associated inflammation, hepatic steatosis, and insulin resistance

Project description:We demonstrated that RORa-deficient staggerer mice (RORasg/sg) fed with a high fat diet (HFD) showed reduced adiposity and hepatic triglyceride levels compared to wild type (WT) littermates and were resistant to the development of hepatic steatosis, adipose-associated inflammation, and insulin resistance. Gene expression profiling showed that many genes involved in triglyceride synthesis and storage, including Cidec, Cidea, and Mogat1, were expressed at much lower levels in liver of RORasg/sg mice. In addition to reduced lipid accumulation, inflammation was greatly diminished in white adipose tissue (WAT) of RORasg/sg mice fed with a HFD. The infiltration of macrophages and the expression of many immune-response and pro-inflammatory genes, including those encoding various chemo/cytokines, toll-like receptors, and TNF signaling proteins, were significantly reduced in RORasg/sg WAT. Moreover, RORasg/sg mice fed with a HFD were protected from the development of insulin resistance. Together, these results indicate that RORa plays a critical role in the regulation of several aspects of metabolic syndrome. Therefore, RORa may provide a novel therapeutic target in the management of obesity and associated metabolic diseases. Liver and white adipose tissue (WAT) total RNAs were purified from 5 WT and 5 RORasg/sg (natural deletion of RORa gene in mice) mice fed with a high fat diet for 6 weeks. Then samples were applied on Agilent mouse genome chip.

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Proteins associated with RORalpha binding element on SULT1E1 gene

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2020-08-26 | PXD016385 | Pride

Nuclear receptor, RORa plays a critical role in obesity-associated inflammation, hepatic steatosis, and insulin resistance

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Transcription profiling of mouse PPAR-apha knockouts reveals gender-specific gene repression of PPAR-alpha knockouts in liver and heart

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