Glucocorticoid Receptor and Lipid Homeostasis

糖皮质激素受体和脂质稳态

基本信息

批准号：
8584629
负责人：
Jen-Chywan Wang
金额：
$ 0.15万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8584629
关键词：
5&apos -AMP-activated protein kinase Adipose tissue Angiopoietins Atherosclerosis Binding Chromatin Structure Complex Development Diabetes Mellitus Fasting Fatty acid glycerol esters Future Gene Expression Profile Gene Silencing Gene Targeting Genes Genetic Transcription Genomics Glucocorticoid Receptor Glucocorticoids Goals Histone Acetylation Homeostasis Hormonal Insulin Intervention Knowledge Lead Ligands Lipids Lipolysis Measures Mediating Metabolic Metabolic Diseases Methylation Modeling Molecular Monitor Mus Nutritional Obesity Organ Pathway interactions Pharmacologic Substance Physiological Play Process Proteins Regulation Research Response Elements Role Signal Transduction Stable Isotope Labeling Stress Techniques Testing Therapeutic Intervention Transcriptional Regulation adenylate kinase cofactor histone modification insight lipid metabolism lipoprotein lipase overexpression research study response steroid hormone transcription factor

项目摘要

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- regulate lipid homeostasis, but also will provide important knowledge that can be applied to develop therapeutic interventions against metabolic diseases, such as obesity and diabetes.

脂质稳态由荷尔蒙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着至关重要的作用。但是，机制这些糖皮质激素作用在很大程度上不清楚。糖皮质激素通过细胞内糖皮质激素受体（GR）。 GR是转录因子，在与配体结合时，可以与基因组糖皮质激素反应元件（GRE）相关联，以调节附近的基因。因此，了解糖皮质激素作用的一个关键步骤是直接识别基因受触发生理反应的GR调节。我们已经确定了GR主要靶基因，禁食诱导的脂肪因子（FIAF，又名A Angiopoietin类样4，Angptl4），它编码一个分泌的抑制脂蛋白脂肪酶并诱导脂肪组织脂解的蛋白质。该提议的目标是检查在糖皮质激素调节的脂质代谢中的作用，并阐明通过包括糖皮质激素，胰岛素和AICAR的不同信号对FIAF基因的转录调节（AMP激活的激酶激活剂）。在AIM 1中，我们将分析糖皮质激素对染色质的影响 FIAF基因的结构，组蛋白乙酰化和甲基化状态。我们还将调查 FOXO1在糖皮质激素和胰岛素反应中的潜在作用在FIAF基因上。而且，我们会的研究AMP激酶是否介导AICAR对糖皮质激活的FIAF的抑制作用基因转录。在AIM 2中，我们将使用缺乏FIAF基因的小鼠探索FIAF在代谢中的作用长期糖皮质激素治疗和禁食引起的变化。除了测量代谢参数，我们还将使用稳定的同位素标记技术监测脂质代谢的速率。总体而言，这项研究不仅会扩大我们对糖皮质激素基础机制的理解调节脂质稳态，但也将提供可以应用的重要知识针对代谢疾病的治疗干预措施，例如肥胖和糖尿病。