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: 7231562
• 负责人: HEATHER A HOSTETLER
• 金额: $ 8.97万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7231562
• 关键词: Acetyl-CoA C-Acetyltransferase; Acyl Coenzyme A; Address; Adrenoleukodystrophy; Affect; Affinity; Agriculture; Apolipoproteins A; Area; Binding; Biochemical; Biochemistry; Biomedical Research; Cardiovascular Diseases; Cell Nucleus; Cholesterol; Cholesterol Homeostasis; DNA Binding; Development; Diabetes Mellitus; Diazepam Binding Inhibitor; Discipline; Disease; Enzymes; FABP1 gene; Fatty Acids; Fellowship; Fishes; Funding; Gene Expression Regulation; Genes; Genetic Transcription; Growth and Development function; Homeostasis; Knowledge; Ligands; Lipids; Lipoproteins; Liver; Mediating; Mentors; Metabolic; Metabolism; Methods; Molecular Biology; Mus; National Research Service Awards; Nuclear; Nuclear Hormone Receptors; Nuclear Receptors; Numbers; Obesity; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Phase; Physiological; Play; Proteins; Public Health; RXR; Range; Regulation; Research; Research Personnel; Research Proposals; Response Elements; Role; Scientist; Solutions; Testing; Transcriptional Regulation; Transgenic Organisms; Tretinoin; United States National Institutes of Health; Unsaturated Fatty Acids; Work; acyl-CoA oxidase; experience; fatty acid oxidation; fatty acid-transport protein; glucose metabolism; insight; insulin signaling; lipid metabolism; lipoprotein lipase; liver fatty acid-binding protein; member; novel strategies; oxidation; programs; receptor; receptor binding; trafficking; transcription factor; translocase; uptake

DESCRIPTION (provided by applicant): The peroxisome proliferator activated-receptor ( (PPAR() plays a central role in energy homeostasis by initiating transcription of multiple genes in fatty acid and glucose metabolism, while concomitantly downregulating genes in insulin signaling. In liver, PPAR( induces transcription of many genes involved in fatty acid degradation by (-oxidation, fatty acid uptake and transport, and lipoprotein metabolism. Thus, PPAR( 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 PPAR( or the effect of these ligands on PPAR( interaction with heterodimer partners. Although it is known that PPAR( must heterodimerize with either the retinoid X receptor (RXR) or the liver X receptor (LXR) prior to binding 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 PPAR( 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 PPAR(-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 PPAR( with L-FABP. Second, the 'independent phase' will: 3. Determine if LXR( binds LCFA-CoA with high affinity, in the physiological range of nuclear LCFA-CoA levels. 4. Elucidate the effect of LCFA-CoA on the molecular interaction of PPAR( with LXR(. It is hoped that the results of this work will provide a mechanistic role of LCFA-CoAs in nuclear receptor regulation. Relevance to Public Health: This work aims at studying a protein whose abnormal expression/regulation is associated with obesity, diabetes, and cardiovascular disease. This research is a step towards the development of new methods and more efficient drugs for the treatment of such disorders.

描述（由申请人提供）： 过氧化物酶体增殖物激活受体（（（PPAR（PPAR（）通过在脂肪酸和葡萄糖代谢中的多个基因的转录中引发多个基因的转录，在能量稳态中起着核心作用，同时在胰岛素信号中下调基因，同时下调基因在胰岛素信号中。脂蛋白代谢。在PPAR上的配体（与异二聚体伴侣的相互作用。 Furthermore, the effect of PPAR( 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 PPAR(-mediated transcription of genes is regulated by long-chain fatty acyl-CoAs (LCFA-CoA). 2. Determine the effect of LCFA-CoA on the molecular PPAR的相互作用（第二，“独立阶段”的相互作用：3。确定LXR是否在核LCFA-COA水平的生理范围内确定LXR（结合LCFA-COA具有高亲和力的LCFA-COA）。4。阐明LCFA-COA对LCFA-COA对PPAR的相互作用的作用（与LXR（LC）的作用（lc（IT。受体调节。 与公共卫生的相关性：这项工作旨在研究一种蛋白质，其异常表达/调节与肥胖，糖尿病和心血管疾病有关。这项研究是迈向开发新方法和更有效的药物来治疗此类疾病的一步。