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.
Highlights
GLUCOCORTICOIDS, steroid hormones produced by and secreted from the adrenal cortex, are essential for the maintenance of metabolic homeostasis both in the basal state and in response to stress [1,2]
We measured the relative mRNA expression of LXRa and glucocorticoid receptor (GR) using the acidic ribosomal phosphoprotein P0 (RPLP0) as an internal control, calculated relative ratios of LXRa mRNA vs. GR mRNA, and confirmed that the transcriptional changes observed were due to alteration in the expressions of these NRs (Fig. 1A and 1B, lower panels)
We found that the repressive effect of LXRa on GR-induced transcriptional activity was associated with the presence of its DBD, while this domain of LXRa was critical for binding to the glucocorticoid response element (GRE) (Fig. 6C), These results indicate that LXRa competes with GR for binding to GREs and subsequent activation of transcription via its DBD
Summary
GLUCOCORTICOIDS, steroid hormones produced by and secreted from the adrenal cortex, are essential for the maintenance of metabolic homeostasis both in the basal state and in response to stress [1,2]. These hormones exert their actions in almost all tissues and organs, and strongly influence intermediary carbohydrate, lipid and protein metabolism [3]. The glucocorticoid-GR complex translocates from the cytoplasm into the nucleus and binds its specific DNA recognition sequences, the glucocorticoid response elements (GREs), located in the regulatory regions of glucocorticoidresponsive genes or interacts with other transcription factors to modulate the latter’s transcriptional activities on their target genes by attracting numerous co-factor molecules and protein complexes to the respective transcription initiation complexes [11,12]
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