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: 8731890
• 负责人: Ji Miao
• 金额: $ 9万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-09 至 2016-08-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8731890
• 关键词: ATP-Binding Cassette Transporters; Adult; Affect; Agonist; Binding Proteins; Cardiovascular Diseases; Chemicals; Cholesterol; Cholesterol Homeostasis; Complex; DNA Binding; Data; Defect; Diet; Disease; Epidemic; Fatty Liver; Fatty acid glycerol esters; Fatty-acid synthase; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Goals; Hepatic; Hepatocyte; Hypertriglyceridemia; Insulin; Insulin Receptor; Insulin Resistance; Knock-out; Knowledge; Ligands; Liver; 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; mTOR protein; mortality; novel; promoter; public health relevance; receptor; 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）是美国发病和死亡的主要原因。肥胖和代谢综合征相关的胰岛素抵抗影响着美国三分之一以上的成年人，会导致脂肪生成增加、高甘油三酯血症以及心血管疾病风险增加两倍以上。然而，胰岛素抵抗增加CVD的分子和机制尚不清楚。肝脏 X 受体 (LXR) 是一种核受体，在控制脂质和胆固醇代谢中发挥核心作用。 LXR 可能在高胰岛素血症、肥胖肝脏中被激活，因为 LXR 的脂肪生成靶标，例如主要的脂肪生成转录因子甾醇反应元件结合蛋白 1c (SREBP1c)，以 LXR 依赖性方式组成型激活。然而，LXR 胆固醇流出靶点，例如 ATP 结合盒转运蛋白、ACBG5 和 ABCG8，在胰岛素抵抗状态下不会被诱导。因此，我们假设胰岛素选择性激活 LXR 诱导其脂肪生成靶点转录的能力，并且这种调节在胰岛素抵抗状态下仍然活跃。该提案的目的是确定胰岛素如何调节 LXR，这种调节在胰岛素抵抗状态下如何改变，以及 LXR 对胰岛素抵抗状态下观察到的脂肪生成和胆固醇流出基因表达变化的贡献。因此，我们建议首先确定胰岛素在 K99 阶段激活 LXR 的信号通路和机制。有了这些知识，我们将确定胰岛素抵抗如何差异性地改变 R00 期脂肪生成和胆固醇流出基因调节中的 LXR 活性。我们期望我们提出的研究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见解，并有可能提供胰岛素抵抗促进CVD的新机制。此外，通过了解脂肪生成和胆固醇流出靶标的转录如何分离，我们也许能够开发新的疗法，通过 LXR 选择性激活胆固醇流出靶标，而不激活脂肪生成。

项目成果

TAZ inhibits glucocorticoid receptor and coordinates hepatic glucose homeostasis in normal physiological states.

TAZ 抑制糖皮质激素受体并协调正常生理状态下的肝脏葡萄糖稳态。

• DOI: 10.7554/elife.57462
• 发表时间: 2021-10-08
• 期刊: eLife
• 影响因子: 7.7
• 作者: Xu S;Liu Y;Hu R;Wang M;Stöhr O;Xiong Y;Chen L;Kang H;Zheng L;Cai S;He L;Wang C;Copps KD;White MF;Miao J
• 通讯作者: Miao J