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

University of Southern Denmark Multifaceted Control of GR Signaling and Its Impact on Hepatic Transcriptional Networks and Metabolism Præstholm, Stine M.; Correia, Catarina M.; Grøntved, Lars Published in: Frontiers in Endocrinology DOI: 10.3389/fendo.2020.572981 Publication date: 2020 Document version: Final published version Document license: CC BY Citation for pulished version (APA): Præstholm, S. M., Correia, C. M., & Grøntved, L. (2020). Multifaceted Control of GR Signaling and Its Impact on Hepatic Transcriptional Networks and Metabolism. Frontiers in Endocrinology, 11, [572981]. https://doi.org/10.3389/fendo.2020.572981 Go to publication entry in University of Southern Denmark's Research Portal Terms of use This work is brought to you by the University of Southern Denmark. Unless otherwise specified it has been shared according to the terms for self-archiving. If no other license is stated, these terms apply: • You may download this work for personal use only. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying this open access version If you believe that this document breaches copyright please contact us providing details and we will investigate your claim. Please direct all enquiries to [email protected] Download date: 29. Sep. 2021 REVIEW published: 08 October 2020 doi: 10.3389/fendo.2020.572981 Multifaceted Control of GR Signaling and Its Impact on Hepatic Transcriptional Networks and Metabolism Stine M. Præstholm †, Catarina M. Correia † and Lars Grøntved* Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark 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 Edited by: challenges in key metabolic organs like the liver. In the liver, GR is known to regulate Nicolas Venteclef, Sorbonne Universités, France the transcription of key enzymes in glucose and lipid metabolism and contribute to the Reviewed by: regulation of circadian-expressed genes. Insights to the modes of GR regulation and Andrew C. B. Cato, the underlying functional mechanisms are key for understanding diseases and for the Karlsruhe Institute of Technology (KIT), Germany development of improved clinical uses of GCs. The activity and function of GR is regulated Dino Moras, at numerous levels including ligand availability, interaction with heat shock protein (HSP) INSERM U964 Institut de Génétique et complexes, expression of GR isoforms and posttranslational modifications. Moreover, de Biologie Moléculaire et Cellulaire (IGBMC), France recent genomics studies show functional interaction with multiple transcription factors *Correspondence: (TF) and coregulators in complex transcriptional networks controlling cell type-specific Lars Grøntved gene expression by GCs. In this review we describe the different regulatory steps [email protected] important for GR activity and discuss how different TF interaction partners of GR †These authors have contributed selectively control hepatic gene transcription and metabolism. equally to this work Keywords: Glucocorticoid receptor, chromatin, transcription, metabolism, liver Specialty section: This article was submitted to Molecular and Structural INTRODUCTION Endocrinology, a section of the journal Any living organism must adapt and respond to the surrounding environment to maintain Frontiers in Endocrinology its existence. For multicellular organisms such as mammals, this includes daily transitions Received: 15 June 2020 between different physiological conditions including sleep/awake, fasted/fed, and physical Accepted: 03 September 2020 inactivity/activity. Moreover, occasional response to environmental changes such as confinement, Published: 08 October 2020 predator stress, extreme temperatures, inflammation and prolonged lack of food is critical for Citation: survival. Glucocorticoids (GCs) serve as important endocrine signaling molecules controlling Præstholm SM, Correia CM and many molecular signaling pathways that enable cells in the organism to respond to different Grøntved L (2020) Multifaceted extrinsic cues. This is particularly evident for cellular responses in the arousal state including the Control of GR Signaling and Its Impact on Hepatic Transcriptional Networks transitions mentioned above. Importantly, pathophysiological conditions leading to dysfunctional and Metabolism. GC signaling have dramatic effects on many important biological functions including development, Front. Endocrinol. 11:572981. inflammatory response, reproduction, cognitive function, anxiety, circadian entrainment, doi: 10.3389/fendo.2020.572981 cardiovascular regulation and cellular metabolism in a tissue-specific manner (1). For example, Frontiers in Endocrinology | www.frontiersin.org 1 October 2020 | Volume 11 | Article 572981 Præstholm et al. GR Regulatory Networks uncontrolled GC secretion observed in Cushing’s syndrome in the genome in synergy with cell-specific TFs, coregulators leads to metabolic complications such as type 2 diabetes and regulatory RNAs. In this review we will discuss all three and osteoporosis, which are also observed in situations of regulatory aspects of GR signaling with a specific focus on GR prolonged treatment with GCs. In contrast, conditions of low GC interaction with the genome. We will primarily refer to studies production, seen in Addison’s disease, are associated with muscle from mouse liver tissue to discuss recent insights to hepatic gene weakness, low blood pressure and weight loss (2). regulatory networks and metabolism controlled by GCs. This will Glucocorticoids exert their actions primarily by binding to specifically be related to the hepatic transcriptional response to the glucocorticoid receptor (GR or Nr3c1), which is expressed the circadian rhythm, feeding and fasting. in most cells in mammals. Yet, GCs have highly tissue/cell- specific effects regulated by multiple mechanisms. As a DNA- binding transcription factor (TF), GR is primarily involved in REGULATION OF GLUCOCORTICOID the control of gene expression, with transcription of GR target SECRETION AND AVAILABILITY IN THE genes in a given cell being controlled by three overall mechanisms CELL (Figure 1). First, activity of GR is directly correlated with the amount of GC molecules available in the cell. This is controlled Glucocorticoids (cortisol in humans; corticosterone in rodents) by adrenal GC synthesis and local availability of GCs in the are steroid hormones secreted circadianly by the adrenal cortex. cell. Second, expression of active GR in the nucleus determines Their daily levels peak immediately before the active phase (early the molecular response to GCs. This is regulated by GR morning for humans; early evening for rodents) in anticipation of turnover (synthesis and breakdown), expression of different GR a waking state, but also in quick response to external stimuli such isoforms, posttranslational modifications (PTMs) and nuclear as stress, hypoglycemia and exercise (3, 4). The hypothalamic- translocation. Third, genomic action of GR is controlled by pituitary-adrenal (HPA) axis controls and maintains GC cell type-specific accessibility of GR response elements (GRE) secretion into the bloodstream (Figure 1A). The hypothalamus 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. Frontiers in Endocrinology | www.frontiersin.org 2 October 2020 | Volume 11 | Article 572981 Præstholm et al. GR Regulatory Networks produces corticosteroid-releasing hormone (CRH), stimulating can act as SCN-gated mediators of the light stimuli to entrain the pituitary gland to secrete adrenocorticotropic hormone metabolic-responsive peripheral clocks (5). The ubiquity of GR (ACTH), which in turn promotes GC secretion by the adrenal expression and the marked circadian secretion of GCs imply that gland (5). As many other hormones, including growth hormone these are efficient SCN-driven synchronizers of peripheral clocks and insulin (6, 7), GCs are secreted in an ultradian pattern with and, specifically in the liver, are fundamental for the circadian pulsatile secretion once every 60 to 90 min, as a result of feedback expression of metabolic genes, even with contribution from other and feedforward mechanisms between ACTH, CRH and GC hormonal signals and entrainment factors (3, 4, 23). However, secretion keeping GC levels in a physiological range (4, 8, 9). GCs do not affect the central clock, since GR is not expressed in The circadian secretion of GCs results

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