Quantitative tissue-specific dynamics of in vivo GILZ mRNA expression and regulation by endogenous and exogenous glucocorticoids

Abstract

Glucocorticoids (GC) are steroid hormones, which regulate metabolism and immune function. Synthetic GCs, or corticosteroids (CS), have appreciable clinical utility via their ability to suppress inflammation in immune-mediated diseases like asthma and rheumatoid arthritis. Recent work has provided insight to novel GC-induced genes that mediate their anti-inflammatory effects, including glucocorticoid-induced leucine zipper (GILZ). Since GILZ comprises an important part of GC action, its regulation by both drug and hormone will influence CS therapy. In addition, GILZ expression is often employed as a biomarker of GC action, which requires judicious selection of sampling time. Understanding the in vivo regulation of GILZ mRNA expression over time will provide insight into both the physiological regulation of GILZ by endogenous GC and the dynamics of its enhancement by CS. A highly quantitative qRT-PCR assay was developed for measuring GILZ mRNA expression in tissues obtained from normal and CS-treated rats. This assay was applied to measure GILZ mRNA expression in eight tissues; to determine its endogenous regulation over time; and to characterize its dynamics in adipose tissue, muscle, and liver following treatment with CS. We demonstrate that GILZ mRNA is expressed in several tissues. GILZ mRNA expression in adipose tissue displayed a robust circadian rhythm that was entrained with the circadian oscillation of endogenous corticosterone; and is strongly enhanced by acute and chronic dosing. Single dosing also enhanced GILZ mRNA in muscle and liver, but the dynamics varied. In conclusion, GILZ is widely expressed in the rat and highly regulated by endogenous and exogenous GCs.

Low expression of the GILZ may contribute to adipose inflammation and altered adipokine production in human obesity

“…Consistent with this in vitro result, preliminary data show that GILZ mRNA levels are also increased by 2- to 3-fold in human adipose tissue in vivo 3.5 h after cortisol administration (K. Karastergiou, M-J. Lee, and S. K. Fried, unpublished observation), similar to a recent study showing that glucocorticoids induce GILZ mRNA levels in rat adipose tissue in vivo (34), and supporting the physiological relevance of our findings in cultured human adipocytes.…”

Functional proteomic analysis of corticosteroid pharmacodynamics in rat liver: Relationship to hepatic stress, signaling, energy regulation, and drug metabolism

“…Both proteins display dynamic behavior that is similar to numerous mRNAs whose expression is enhanced by MPL in liver, including the prototypic CS-regulated gene, tyrosine aminotransferase (TAT) [7]. Mechanistically, such patterns of enhancement are often observed for proteins encoded by gene sequences containing glucocorticoid-response elements (GREs) in their promoter region [28]. While metallotheonein-1 indeed contains a pair of adjacent GREs in its promoter region [29], conflicting mechanistic explanations may exist for tryptophan 2,3-dioxygenase.…”

Elevated Hypothalamic Glucocorticoid Levels Are Associated With Obesity and Hyperphagia in Male Mice

“…Indeed, our novel findings show that Gcs do down-regulate the GR in our model, but most importantly, the receptor is not completely down-regulated. Gcs can still act in the hypothalamus to increase known target genes such as GILZ, a transcription factor, known to be sensitive to Gc activation (22, 23), and also maintain the decreases in 11β-HSD1 and GR. Although there is a 50% decrease in GR expression at 4 weeks, GILZ, is increased at 24 hours (our unpublished data) and remains elevated after 4 weeks of treatment.…”