Abstract
Glucocorticoids (GCs) and the glucocorticoid receptor (GR) are important regulators of development, inflammation, stress response and metabolism, demonstrated in various diseases including Addison's disease, Cushing's syndrome and by the many side effects of prolonged clinical administration of GCs. These conditions include severe metabolic challenges in key metabolic organs like the liver. In the liver, GR is known to regulate the transcription of key enzymes in glucose and lipid metabolism and contribute to the regulation of circadian-expressed genes. Insights to the modes of GR regulation and the underlying functional mechanisms are key for understanding diseases and for the development of improved clinical uses of GCs. The activity and function of GR is regulated at numerous levels including ligand availability, interaction with heat shock protein (HSP) complexes, expression of GR isoforms and posttranslational modifications. Moreover, recent genomics studies show functional interaction with multiple transcription factors (TF) and coregulators in complex transcriptional networks controlling cell type-specific gene expression by GCs. In this review we describe the different regulatory steps important for GR activity and discuss how different TF interaction partners of GR selectively control hepatic gene transcription and metabolism.
Highlights
Any living organism must adapt and respond to the surrounding environment to maintain its existence
In the liver, LXRα binds GR response elements (GRE) together with its heterodimerization partner RXRα, thereby potentially competing with glucocorticoid receptor (GR) for binding to the same sites leading to differential regulation of genes involved in glucose metabolism [112]
The GR-PPARα interactions in the liver include co-localization to chromatin and coregulation of genes involved in lipid and glucose metabolism [150]
Summary
Any living organism must adapt and respond to the surrounding environment to maintain its existence. Several confirmed composite GR-TF interactions have been found to impact GR activity and hepatic metabolism, including C/EBPβ, E47, STAT5, and LXRβ, which are required for GR recruitment to specific sites [26, 72, 110, 113], in accordance with the model for assisted loading. GR tethering to the BMAL1-CLOCK complex is suggested to repress hepatic Rev-erbα expression [115], demonstrating how GR and the molecular circadian clock interconnect to regulate shared gene programs.
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