Glucocorticoid Receptor and Lipid Homeostasis

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DESCRIPTION (provided by applicant): Lipid homeostasis is exquisitely controlled by hormonal and nutritional signals. Glucocorticoids are steroid hormones that play a critical role in regulating lipid homeostasis. However, the mechanisms underlying these glucocorticoid effects are largely unclear. Glucocorticoids convey their signals through an intracellular glucocorticoid receptor (GR). GR is a transcription factor, which upon binding to ligands, can associate with genomic glucocorticoid response element (GRE) to regulate the transcription of nearby genes. Thus, one critical step to understand glucocorticoid action is to identify genes directly regulated by GR that trigger the physiological response. We have identified a GR primary target gene, fasting-induced adipose factor (FIAF, a.k.a. angiopoietin-like 4, ANGPTL4), which encodes a secreted protein that inhibits lipoprotein lipase and induces adipose tissue lipolysis. The goals of this proposal are to examine the role in glucocorticoid-regulated lipid metabolism and to elucidate the mechanisms of transcriptional regulation of FIAF gene by distinct signals that include glucocorticoids, insulin and AICAR (an AMP-activated kinase activator). In Aim 1, we will analyze the effects of glucocorticoids on chromatin structure, and histone acetylation and methylation status of FIAF gene. We will also investigate the potential role of FOXO1 in glucocorticoid and insulin response on FIAF gene. Moreover, we will investigate whether AMP kinase mediates the inhibitory effect of AICAR on glucocorticoid-activated FIAF gene transcription. In Aim 2, we will use mice lacking FIAF gene to explore the role of FIAF in metabolic changes induced by long-term glucocorticoid treatment and fasting. In addition to measure metabolic parameters, we will also monitor the rate of lipid metabolism using stable isotope labeling technique. Overall, this research not only will expand our understanding on mechanisms underlying glucocorticoid-regulated lipid homeostasis, but also will provide important knowledge that can be applied to develop therapeutic interventions against metabolic diseases, such as obesity and diabetes. PUBLIC HEALTH RELEVANCE: Disturbance of lipid homeostasis is associated with the development of a wide variety of metabolic diseases, such as diabetes, obesity and atherosclerosis. Glucocorticoids are steroid hormones that play an important role in regulation of lipid metabolism. This proposed research is to understand the molecular mechanisms of glucocorticoid action on lipid metabolism and to provide new insights for future pharmaceutical interventions against metabolic diseases.