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.

Liver X receptor agonists decrease ENaC-mediated sodium transport in collecting duct cells

“…However, the precise mechanism how LXR activation inhibits ENaC mRNA expression is unknown. A previous study reported that LXRs repressed glucocorticoid receptor-stimulated transactivation of glucocorticoid response element-driven promoters in a genespecific fashion (21). Therefore, it is possible that LXRs may directly suppress promoter activity of ENaC.…”

Metabolic comorbidities in Cushing's syndrome

“…Indeed, an interplay has been found between GR and liver X receptors (LXRs), which are known to heterodimerise with the retinoid X receptor (RXR) to regulate cholesterol turnover and glucose metabolism. In a recent study, the LXRs/RXR complex reduced the transcriptional activity of GR, since LXR activation was able to reduce dexamethasonestimulated elevation of circulating glucose in rats and suppress dexamethasone-induced mRNA expression of hepatic glucose-6-phosphatase in rats, mice and human hepatoma cells (26). Moreover, the PPARa signalling pathway, which is required to suppress glucose-stimulated insulin secretion during fasting, has been found to be involved in the dexamethasone-mediated insulin resistance in the liver (27).…”

Minireview: New Molecular Mediators of Glucocorticoid Receptor Activity in Metabolic Tissues

“…In vivo studies in rodents have shown that activation of LXR␣ decreases liver levels of these genes along with hepatic glucose production (68,69). It was recently shown that treatment of hepatoma cells with LXR ligands also suppressed GC-induced Pepck and G6pc expression (70). In agreement, dosing the rats for three days with an LXR ligand (GW3965) attenuated the increase in plasma glucose that is observed after a single dose of Dex (70).…”