Regulation of triglyceride metabolism by glucocorticoid receptor

Jen-Chywan Wang,Charles A Harris,Taiyi Kuo,Nora E Gray

doi:10.1186/2045-3701-2-19

Abstract

Glucocorticoids are steroid hormones that play critical and complex roles in the regulation of triglyceride (TG) homeostasis. Depending on physiological states, glucocorticoids can modulate both TG synthesis and hydrolysis. More intriguingly, glucocorticoids can concurrently affect these two processes in adipocytes. The metabolic effects of glucocorticoids are conferred by intracellular glucocorticoid receptors (GR). GR is a transcription factor that, upon binding to glucocorticoids, regulates the transcriptional rate of specific genes. These GR primary target genes further initiate the physiological and pathological responses of glucocorticoids. In this article, we overview glucocorticoid-regulated genes, especially those potential GR primary target genes, involved in glucocorticoid-regulated TG metabolism. We also discuss transcriptional regulators that could act with GR to participate in these processes. This knowledge is not only important for the fundamental understanding of steroid hormone actions, but also are essential for future therapeutic interventions against metabolic diseases associated with aberrant glucocorticoid signaling, such as insulin resistance, dyslipidemia, central obesity and hepatic steatosis.

Highlights

The balance of lipogenesis and lipolysis is vital for maintaining triglyceride (TG) homeostasis in mammals
Endogenous unliganded LXRβ is required for a maximal glucocorticoid receptors (GR) occupancy on the glucocorticoid response elements (GRE) of gluconeogic genes, whereas Liver X receptor (LXR) ligands appear to suppress glucocorticoid-activated gluconeogic gene transcription by inhibiting the recruitment of GR to the GREs of these genes. In this manuscript, we review glucocorticoid-regulated genes participating in the modulation of TG metabolism
It is important to note that only a handful of identified GR primary target genes have been shown to mediate glucocorticoid effects on TG metabolism in vivo

Summary

Introduction

The balance of lipogenesis and lipolysis is vital for maintaining triglyceride (TG) homeostasis in mammals. Free FA (FFA) are mobilized to skeletal muscle and liver to be oxidized and used as energy, whereas glycerol becomes the substrate for hepatic gluconeogenesis Such metabolic adaptation is critical for the survival of mammals during fasting and starvation. Excess/ chronic glucocorticoids increase the circulating FFA and induce ectopic lipid accumulation in skeletal muscle and liver, all are associated with insulin resistance [9,10]. Recent studies applying chromatin immunoprecipitation sequencing (ChIPseq) have identified genome-wide GR binding regions (GBRs) in distinct cell types [7,20,21,22] In these GBRs, the classical GRE sequences are highly represented, albeit small differences exist between them [7,20,21,22] (Table 1). The human ACACA and ACACB genes contain 3 (PI-III) and 2 (PI-II) alternative promoters, Acetyl-CoA

T3-L1 mouse Adipocyte

Conclusion

Findings

Berdanier CD