Glucocorticoid Receptor and Lipid Homeostasis

描述（由申请人提供）：脂质稳态由激素和营养信号精确控制。糖皮质激素是类固醇激素，在调节脂质稳态中起关键作用。然而，这些糖皮质激素作用的机制在很大程度上还不清楚。糖皮质激素通过细胞内糖皮质激素受体（GR）传递其信号。GR是一种转录因子，与配体结合后，可与基因组糖皮质激素反应元件（GRE）结合，调节附近基因的转录。因此，了解糖皮质激素作用的一个关键步骤是鉴定直接受GR调节的触发生理反应的基因。我们已经鉴定了GR主要靶基因，禁食诱导的脂肪因子（FIAF，a.k.a.血管生成素样4，ANGPTL4），其编码抑制脂蛋白脂肪酶并诱导脂肪组织脂解的分泌蛋白。本研究的目的是探讨FIAF基因在糖皮质激素调节脂质代谢中的作用，并阐明FIAF基因通过糖皮质激素、胰岛素和AICAR（一种AMP激活的激酶激活剂）等不同信号进行转录调控的机制。目的一：分析糖皮质激素对染色质结构、FIAF基因组蛋白乙酰化和甲基化状态的影响。我们还将研究FOXO 1在FIAF基因对糖皮质激素和胰岛素反应中的潜在作用。此外，我们将研究AMP激酶是否介导AICAR对糖皮质激素激活的FIAF基因转录的抑制作用。在目标2中，我们将使用缺乏FIAF基因的小鼠来探索FIAF在长期糖皮质激素治疗和禁食引起的代谢变化中的作用。除了测量代谢参数外，我们还将使用稳定同位素标记技术监测脂质代谢速率。总的来说，这项研究不仅将扩大我们对糖皮质激素调节脂质稳态的机制的理解，而且还将提供重要的知识，可用于开发针对代谢疾病（如肥胖和糖尿病）的治疗干预措施。公共卫生相关性：脂质稳态的紊乱与多种代谢疾病的发展相关，例如糖尿病、肥胖和动脉粥样硬化。糖皮质激素是一种在调节脂质代谢中起重要作用的类固醇激素。这项研究旨在了解糖皮质激素对脂质代谢作用的分子机制，并为未来代谢性疾病的药物干预提供新的见解。

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.