Multifaceted Control of GR Signaling and Its Impact on Hepatic Transcriptional Networks and Metabolism

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.

Keywords: Glucocorticoid receptor; chromatin; liver; metabolism; transcription.

Figure 1

Overview of the regulatory levels affecting GR activity in the control of hepatic transcription. (A) Circadian and ultradian synthesis of GCs is controlled by the HPA axis in response to external stimuli including feeding, stress, light and circadian timekeepers. Availability of active GCs is further influenced by binding to the serum protein CBG and by intracellular conversion catalyzed by the enzyme 11β-HSD1/2. (B) Once in the cell, GCs are bound by the GR with an affinity that is conditioned by association with chaperone complexes containing HSPs, expression of specific GR isoforms and GR protein turnover. (C) GR exerts its action after translocation to the nucleus, where it binds GRE sequences in the DNA to regulate transcription of target genes as a result of dynamic interaction with different TFs and coregulators.

Figure 2

Direct and indirect GR-DNA interactions. (A) GR interacts dynamically with DNA. Freely diffusing GR occupies chromatin with residence time in milliseconds, whereas GR binding at specific regions of chromatin is measured in the order of seconds. (B) GR interacts directly with DNA by binding to canonical GRE (nGnACAnnnTGTnCn), half-sites (nGnACA) and nGRE (CTCC(n)₀₋₂GGAGA) or indirectly by tethering to DNA-bound TFs by protein-protein interactions. (C) TFs can assist the loading of GR, or vice versa, by facilitating an accessible chromatin environment at the regulatory site.

Figure 3

GR interaction with TFs on chromatin. (A) GR and TFs co-occupy enhancers through homodimeric or monomeric GR binding together with TFs at composite sites, by heterodimerization and through tethering. (B) GR- and TF-mediated recruitment of coactivators (CoA) and/or corepressors (CoR) to co-occupied regulatory sites controls the net enhancer activity. (C) Indirect GR-TF interaction involves TF cascades, where the expression of GR regulates the expression of TF or vice versa.

Figure 4

Examples of TFs interacting with GR regulating hepatic metabolism. GR interacts with different TFs to regulate specific processes in hepatic glucose, fatty acid, lipid, and bile acid metabolism.