The role of long chain acyl-CoAs in nuclear receptor regulation

长链酰基辅酶A在核受体调节中的作用

• 批准号: 7938706
• 负责人: HEATHER A HOSTETLER
• 金额: $ 24.87万
• 依托单位: WRIGHT STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7938706
• 关键词: Acyl Coenzyme A; Address; Affinity; Award; Binding; Cardiovascular Diseases; Cell Nucleus; DNA; Development; Diabetes Mellitus; Disease; FABP1 gene; Fatty Acids; Genes; Genetic Transcription; Homeostasis; LXRalpha protein; Ligands; Lipids; Lipoproteins; Liver; Mediating; Mentors; Metabolic; Metabolism; Methods; Nuclear; Nuclear Receptors; Obesity; PPAR alpha; Peroxisome Proliferator-Activated Receptors; Phase; Physiological; Play; Proteins; RXR; Regulation; Research; Response Elements; Role; Transcriptional Regulation; Work; fatty acid oxidation; glucose metabolism; insulin signaling; receptor; uptake

The peroxisome proliferator-activated receptor a (PPARalpha) plays a central role in energy homeostasis by initiating transcription of multiple genes in fatty add and glucose metabolism, while concomitantaly downregulating genes in insulin signaling. In liver, PPARa induces transcription of many genes involved in fatty acid degradation by b-oxidation, fatty acid uptake and transport, and lipoprotein metabolism. Thus, PPARalpha is responsible for control of a number of lipid metabolic proteins that may contribute to obesity, diabetes, lipotoxicity, and subsequent cardiovascular disorders. However, relatively little is known regarding either the mechanisms that regulate the availability of endogenous fatty acyl-CoA ligands to the nucleus for interaction with PPARa or the effect of these ligands on PPARalpha interaction with heterodimer partners. Although it is known that PPARa must heterodimerize with either the retinoid X receptor (RXR) or the liver X receptor (LXR) prior to bidning DNA response elements for transcriptional regulation, surprisingly little is known about the effect of endogenous ligands on the choice of heterodimer partners. Furthermore, the effect of PPARalpha ligands on heterodimer partners is incompletely resolved. In order to address these issues, this proposal is focused in two phases: First, the 'mentored phase' will: 1. Resolve whether PPARa-mediated transcription of genes is regulated by long-chain fatty acyl-CoAs (LCFA-CoA). 2. Determine the effect of LCFA-CoA on the molecular interaction of PPARa with L-FABP. Second, the 'independent phase' w^ill: 3. Determine if LXRa binds LCFA-CoA with high affinity, in the physiological range of nulcear LCFA-CoA levels. 4. Elucidate the effect of LCFA-CoA on the molecular interaction of PPARa with LXRa. It is hoped tha the results of this work will provide a mechanistic role of LCFA-CoA in nuclear receptor regulation.

过氧化物酶体增殖物激活的受体A（PPARALPHA）通过在脂肪添加和葡萄糖代谢中启动多个基因的转录在能量稳态中起着核心作用，同时伴随着胰岛素信号中基因的下调。在肝脏中，PPARA诱导许多通过B氧化，脂肪酸摄取和转运以及脂蛋白代谢参与脂肪酸降解的基因的转录。因此，pParalpha负责控制许多可能导致肥胖，糖尿病，脂肪毒性和随后的心血管疾病的脂质代谢蛋白。但是，关于调节内源性脂肪酰基配体在细胞核中可用的机制，与PPARA相互作用的机制相对较少，或者这些配体对PPARALPHA与异二聚体伴侣相互作用的影响。尽管众所周知，PPARA必须在出价调节的竞标DNA响应元件之前与类维生素类X受体（RXR）或肝脏X受体（LXR）进行异二聚体，但令人惊讶的是，对于内源性配体对HeteroDimer伴侣选择的影响，知之甚少。此外，pParalpha配体对异二聚体伴侣的影响无法完全解决。为了解决这些问题，该提案集中在两个阶段：首先，“指导阶段”将：1。解决PPARA介导的基因转录是否受长链脂肪脂肪酰基-COAS（LCFA-COA）调节。 2。确定LCFA-COA对PPARA与L-FABP的分子相互作用的影响。其次，“独立阶段” w^ill：3。确定LXRA是否在Nulcear LCFA-COA水平的生理范围内结合具有高亲和力的LCFA-COA。 4。阐明LCFA-COA对PPARA与LXRA的分子相互作用的影响。希望这项工作的结果将提供LCFA-COA在核受体调节中的机械作用。