Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark.
Front Endocrinol (Lausanne). 2020 Oct 8;11:572981. doi: 10.3389/fendo.2020.572981. eCollection 2020.
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.
糖皮质激素（GCs）和糖皮质激素受体（GR）是发育、炎症、应激反应和代谢的重要调节剂，在各种疾病中都有体现，包括艾迪生病、库欣综合征以及长期临床应用 GCs 的许多副作用。这些病症包括肝脏等关键代谢器官的严重代谢挑战。在肝脏中，GR 已知可调节葡萄糖和脂质代谢的关键酶的转录，并有助于调节昼夜节律表达的基因。深入了解 GR 调节的模式和潜在的功能机制对于理解疾病和开发改进的 GCs 临床用途至关重要。GR 的活性和功能受到多个层面的调节，包括配体可用性、与热休克蛋白（HSP）复合物的相互作用、GR 同工型的表达和翻译后修饰。此外，最近的基因组学研究表明，GR 与多个转录因子（TF）和共激活因子在复杂的转录网络中具有功能相互作用，通过 GCs 控制细胞类型特异性基因表达。在这篇综述中，我们描述了对 GR 活性很重要的不同调节步骤，并讨论了 GR 的不同 TF 相互作用伙伴如何选择性地控制肝脏基因转录和代谢。
