title: Liver x receptors regulate the transcriptional activity of the glucocorticoid receptor: implications for the carbohydrate metabolism.
abstract: GLUCOCORTICOIDS are steroid hormones that strongly influence intermediary carbohydrate metabolism by increasing the transcription rate of glucose-6-phosphatase (G6Pase), a key enzyme of gluconeogenesis, and suppress the immune system through the glucocorticoid receptor (GR). The liver X receptors (LXRs), on the other hand, bind to cholesterol metabolites, heterodimerize with the retinoid X receptor (RXR), and regulate the cholesterol turnover, the hepatic glucose metabolism by decreasing the expression of G6Pase, and repress a set of inflammatory genes in immune cells. Since the actions of these receptors overlap with each other, we evaluated the crosstalk between the GR- and LXR-mediated signaling systems. Transient transfection-based reporter assays and gene silencing methods using siRNAs for LXRs showed that overexpression/ligand (GW3965) activation of LXRs/RXRs repressed GR-stimulated transactivation of certain glucocorticoid response element (GRE)-driven promoters in a gene-specific fashion. Activation of LXRs by GW3965 attenuated dexamethasone-stimulated elevation of circulating glucose in rats. It also suppressed dexamethasone-induced mRNA expression of hepatic glucose-6-phosphatase (G6Pase) in rats, mice and human hepatoma HepG2 cells, whereas endogenous, unliganded LXRs were required for dexamethasone-induced mRNA expression of phosphoenolpyruvate carboxylase. In microarray transcriptomic analysis of rat liver, GW3965 differentially regulated glucocorticoid-induced transcriptional activity of about 15% of endogenous glucocorticoid-responsive genes. To examine the mechanism through which activated LXRs attenuated GR transcriptional activity, we examined LXRα/RXRα binding to GREs. Endogenous LXRα/RXRα bound GREs and inhibited GR binding to these DNA sequences both in in vitro and in vivo chromatin immunoprecipitation assays, while their recombinant proteins did so on classic or G6Pase GREs in gel mobility shift assays. We propose that administration of LXR agonists may be beneficial in glucocorticoid treatment- or stress-associated dysmetabolic states by directly and gene-specifically attenuating the transcriptional activity of the GR on glucose and/or lipid metabolism.
authors.affiliation: Unit on Molecular Hormone Action, Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America. nadernancy@hotmail.com
authors.forename: Nancy
authors.initials: N
authors.lastname: Nader
authors.forename: Sinnie Sin Man
authors.initials: SS
authors.lastname: Ng
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Wang
authors.forename: Brent S
authors.initials: BS
authors.lastname: Abel
authors.forename: George P
authors.initials: GP
authors.lastname: Chrousos
authors.forename: Tomoshige
authors.initials: T
authors.lastname: Kino
mesh_terms: D000818:Animals; D001483:Base Sequence; D001565:Benzoates / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D050260:Carbohydrate Metabolism; D045744:Cell Line, Tumor; D017931:DNA Primers; D003907:Dexamethasone / Q000494:pharmacology; D019281:Dimerization; D005260:Female; D020868:Gene Silencing; D008099:Liver / Q000378:metabolism; D000071518:Liver X Receptors; D020411:Oligonucleotide Array Sequence Analysis; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000502:physiology*; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D011965:Receptors, Glucocorticoid / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology*; D059467:Transcriptome
chemical_list: D001565:Benzoates; D001596:Benzylamines; D017931:DNA Primers; C473027:GW 3965; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; C000605215:Nr1h3 protein, rat; D057093:Orphan Nuclear Receptors; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone