Hepatic glucocorticoid-induced transcriptional regulation is androgen-dependent after chronic but not acute glucocorticoid exposure.

Autor: Buurstede JC; Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands., Paul SN; Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands., De Bosscher K; Translational Nuclear Receptor Research, VIB Center for Medical Biotechnology, UGent Department of Biomolecular Medicine, Gent, Belgium., Meijer OC; Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands., Kroon J; Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands.
Jazyk: angličtina
Zdroj: FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2022 Apr; Vol. 36 (4), pp. e22251.
DOI: 10.1096/fj.202101313R
Abstrakt: Glucocorticoids exert their pleiotropic effects by activating the glucocorticoid receptor (GR), which is expressed throughout the body. GR-mediated transcription is regulated by a multitude of tissue- and cell type-specific mechanisms, including interactions with other transcription factors such as the androgen receptor (AR). We previously showed that the transcription of canonical glucocorticoid-responsive genes is dependent on active androgen signaling, but the extent of this glucocorticoid-androgen crosstalk warrants further investigation. In this study, we investigated the overall glucocorticoid-androgen crosstalk in the hepatic transcriptome. Male mice were exposed to GR agonist corticosterone and AR antagonist enzalutamide in order to determine the extent of androgen-dependency after acute and chronic exposure. We found that a substantial proportion of the hepatic transcriptome is androgen-dependent after chronic exposure, while after acute exposure the transcriptomic effects of glucocorticoids are largely androgen-independent. We propose that prolonged glucocorticoid exposure triggers a gradual upregulation of AR expression, instating a situation of androgen dependence which is likely not driven by direct AR-GR interactions. This indirect mode of glucocorticoid-androgen interaction is in accordance with the absence of enriched AR DNA-binding near AR-dependent corticosterone-regulated genes after chronic exposure. In conclusion, we demonstrate that glucocorticoid effects and their interaction with androgen signaling are dependent on the duration of exposure and believe that our findings contribute to a better understanding of hepatic glucocorticoid biology in health and disease.
(© 2022 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)
Databáze: MEDLINE
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