Insulin Regulation of Liver X Receptor in Normal and Insulin Resistant States

正常和胰岛素抵抗状态下肝脏 X 受体的胰岛素调节

• 批准号: 9306322
• 负责人: Ji Miao
• 金额: $ 24.9万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-03 至 2019-08-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9306322
• 关键词: ATP binding cassette transporter 1; ATP-Binding Cassette Transporters; Adult; Affect; Agonist; Binding Proteins; Cardiovascular Diseases; Chemicals; Cholesterol; Cholesterol Homeostasis; Complex; DNA Binding; Data; Defect; Disease; Epidemic; FRAP1 gene; Fatty Liver; Fatty acid glycerol esters; Fatty-acid synthase; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Goals; Health; Hepatic; Hepatocyte; High Fat Diet; Hypertriglyceridemia; Insulin; Insulin Receptor; Insulin Resistance; Knock-out; Knowledge; Ligands; Liver; Liver X Receptor; Luciferases; Mass Spectrum Analysis; Measures; Messenger RNA; Metabolic; Metabolic syndrome; Morbidity - disease rate; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Nuclear Receptors; Obesity; Pathway interactions; Phase; Phosphorylation; Play; Post-Translational Protein Processing; Production; Rattus; Regulation; Reporter; Response Elements; Ribosomal Protein S6 Kinase; Role; Signal Pathway; Signaling Molecule; Sirolimus; Sterols; Transactivation; Transcriptional Regulation; United States; cardiovascular disorder prevention; cardiovascular disorder risk; chromatin immunoprecipitation; db/db mouse; effective therapy; expectation; feeding; inhibitor/antagonist; insight; insulin signaling; lipid biosynthesis; lipid metabolism; mortality; novel; novel therapeutics; promoter; receptor binding; therapy development

DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the United States. Obesity and metabolic syndrome-associated insulin resistance, which affects more than one third of adults in the US, causes increased lipogenesis, hypertriglyceridemia and a greater than 2-fold increase in the risk of CVD. However, the molecules and mechanisms by which insulin resistance increases CVD are not clear. Liver X receptor (LXR) is a nuclear receptor which plays a central role in control of both lipid and cholesterol metabolism. LXR is presumably activated in the hyperinsulinemic, obese liver since the lipogenic targets of LXR, such as sterol response element binding protein 1c (SREBP1c), the master lipogenic transcriptional factor, are constitutively activated in a LXR-dependent manner. However, LXR cholesterol efflux targets, such as the ATP binding cassette transporters, ACBG5 and ABCG8, are not induced in insulin resistant states. Thus, we hypothesize that insulin selectively activates the ability of LXR to induce transcription of its lipogenic targets and that this regulation remains active in insulin resistant state. The objective of this proposal are to determine how insulin regulates LXR, how this regulation is changed in insulin resistant states and the contribution of LXR to the changes in lipogenic and cholesterol efflux gene expression observed in insulin resistant states. Thus we propose to first identify the signaling pathways and mechanisms by which insulin activates LXR in the K99 phase. With such knowledge we will then determine how insulin resistance differentially modifies LXR activity in the regulation of lipogenesis and cholesterol efflux genes in the R00 phase. It is our expectation that the results of our proposed studies will provide important insights into the transcriptional control of lipid and cholesterol metabolism in the insulin resistant state and potentially provide a novel mechanism by which insulin resistance promotes CVD. Moreover, by understanding how transcription of the lipogenic and cholesterol efflux targets can be dissociated, we may be able to develop novel therapies to selectively activate the cholesterol efflux targets via LXR, without activating lipogenesis.

描述（由申请人提供）：心血管疾病（CVD）是美国发病率和死亡率的主要原因。肥胖和代谢综合征相关的胰岛素抵抗会影响美国三分之一以上的成年人，导致脂肪生成增加，高甘油三酸酯血症，CVD风险增加了2倍以上。但是，胰岛素抵抗增加CVD的分子和机制尚不清楚。肝X受体（LXR）是一种核受体，在控制脂质和胆固醇代谢方面起着核心作用。 LXR可能在高胰岛素血症，肥胖的肝脏中激活，因为LXR的脂肪生成靶标，例如固醇反应元件结合蛋白1C（SREBP1C），主要的脂肪生成转录因子是在依赖LXR依赖性方式中组成性激活的。但是，在胰岛素抵抗状态下，LXR胆固醇外排靶标，例如ATP结合盒转运蛋白ACBG5和ABCG8。因此，我们假设胰岛素有选择地激活LXR诱导其脂肪生成靶标的转录的能力，并且该调节在胰岛素耐药态下保持活跃。该提案的目的是确定胰岛素如何调节LXR，胰岛素抵抗状态中该调节的变化以及LXR对在胰岛素耐药态中观察到的脂肪生成和胆固醇外排基因表达的变化的贡献。因此，我们建议首先识别胰岛素在K99期激活LXR的信号传导途径和机制。然后，我们将确定胰岛素抵抗如何在R00期间在调节脂肪生成和胆固醇外排基因的调节中改变LXR活性。我们期望我们提出的研究的结果将为胰岛素抵抗状态下脂质和胆固醇代谢的转录控制提供重要的见解，并有可能提供一种新的机制，胰岛素抵抗可以促进CVD。此外，通过了解如何解离脂肪生成和胆固醇外排靶的转录，我们也许能够开发新的疗法以通过LXR选择性地激活胆固醇外排靶，而无需激活脂肪生成。