Coordination of gut-liver bile acid signaling by FXR

FXR 协调肠-肝胆汁酸信号传导

• 批准号: 9901510
• 负责人: Jongsook Kim Kemper
• 金额: $ 35.69万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9901510
• 关键词: Address; Affect; Bile Acid Biosynthesis Pathway; Bile Acids; Biliary; Binding Sites; ChIP-seq; Cholestasis; Chronic; DNA Binding; Data; Defect; Detergents; Digestion; Disease; Dissociation; Down-Regulation; FGF19 gene; FGFR4 gene; Feedback; Fibrosis; Gene Expression; Genes; Genetic; Genetic Transcription; Genomics; Goals; Hepatic; Hepatobiliary; Hepatotoxicity; Homeostasis; Human; In Vitro; Intestinal Diseases; Intestinal Hormones; Intestines; Knockout Mice; Lead; Lipids; Liver; Liver diseases; Long-Term Effects; Malignant neoplasm of liver; Mediating; Membrane; Metabolic Diseases; Metabolism; Mus; Mutation; Nuclear; Nuclear Envelope; Nuclear Receptors; Nutrient; PPAR alpha; Pathologic; Pathway interactions; Patients; Peroxisome Proliferator-Activated Receptors; Phosphorylation; Physiological; Play; Post-Translational Protein Processing; Primary biliary cirrhosis; RXR; Regulation; Regulator Genes; Repression; Research; Role; Sampling; Signal Transduction; Signaling Molecule; Testing; Tissues; Transcription Repressor; Transcriptional Regulation; Translating; Viral; base; bile acid metabolism; cholestatic liver disease; diagnostic biomarker; experimental study; feeding; in vivo; insight; liver injury; mouse model; mutant; new therapeutic target; novel; novel therapeutics; prevent; receptor; reconstitution; response; synthetic enzyme; therapeutic biomarker

Project Summary The overall goal of this application is to determine the interplay between the liver and intestine in the regulation of fed-state metabolism with emphasis on bile acid (BA) metabolism. BAs function as physiological detergents to aid digestion of lipid nutrients but also function as signaling molecules that profoundly impact metabolism by activating nuclear and membrane BA receptors and also by mediating induction of intestinal FGF15/19 (human FGF19; mouse FGF15). BAs in excess are toxic so that their levels must be tightly controlled and the BA nuclear receptor FXR plays a key role in this regulation. Despite recent advances, the mechanisms underlying the interplay between the liver and intestine mediated by BAs and FGF15 to regulate BA levels, in particular hepatic expression of Cyp7a1, the rate-limiting BA synthetic enzyme, are not well understood. We have preliminary evidence that FGF15-mediated phosphorylation by Src of FXR plays an important role in this interplay. Based on our preliminary data, we hypothesize that Src phosphorylation of FXR at Tyr-67 is mediated by FGF15 signaling under physiological conditions and that Y67FXR phosphorylation is important for gene-selective transcriptional regulation to reduce liver BA levels and terminate FGF15 signaling. To test this hypothesis, we propose the following Specific Aims: 1) Examine the in vivo role of Src phosphorylation of FXR in regulating BA levels, protecting against hepatobiliary defects in normal mice and in mice challenged with biliary insults, and human relevance by examining FXR and Src and their phosphorylated forms in liver samples from primary cholestasis patients. 2) Define the function and mechanisms of FXR phosphorylation by FGF15- and BA-activated Src in the regulation of BA metabolism and 3) determine the role of FGF15-mediated phosphorylation of FXR, in coordination with PPARα, in terminating FGF15 signaling. Multiple in vitro and in vivo approaches will be used, including genetic and virally generated mouse models and ChIP-seq genomic analysis to identify FXR binding sites globally in mice treated with FGF19. Our expertise on post-translational modifications of nuclear receptors and transcriptional regulation of BA metabolism uniquely qualifies us to address this important research question of the role of posttranslational phosphorylation of FXR in regulation of BA metabolism. Our proposal will determine the novel function and mechanisms of FGF15- induced phosphorylation of FXR, and provide new potential therapeutics and diagnostic markers for BA- and FGF15-related diseases, including cholestatic liver diseases.

项目概要 该应用的总体目标是确定肝脏和肠道在调节中的相互作用 餐后代谢，重点是胆汁酸（BA）代谢。 BA 作为生理洗涤剂 有助于脂质营养物质的消化，同时也可作为信号分子，通过以下方式深刻影响新陈代谢： 激活核和膜 BA 受体，还通过介导肠道 FGF15/19（人 FGF19；小鼠 FGF15)。过量的 BA 有毒，因此必须严格控制其含量，并且 核受体 FXR 在这种调节中起着关键作用。尽管最近取得了进展，但其背后的机制 BA 和 FGF15 介导的肝脏和肠道之间的相互作用来调节 BA 水平，特别是 Cyp7a1（限速 BA 合成酶）的肝脏表达尚不清楚。我们有 初步证据表明 FGF15 介导的 FXR Src 磷酸化在此过程中发挥重要作用 相互作用。根据我们的初步数据，我们假设 FXR 在 Tyr-67 处的 Src 磷酸化是 在生理条件下由 FGF15 信号传导介导，并且 Y67FXR 磷酸化是 对于降低肝脏 BA 水平和终止 FGF15 的基因选择性转录调控很重要 发信号。为了检验这一假设，我们提出以下具体目标：1）检查 Src 的体内作用 FXR 磷酸化可调节 BA 水平，防止正常小鼠和小鼠的肝胆缺陷 通过检查 FXR 和 Src 及其磷酸化，对遭受胆道损伤的小鼠以及人类相关性进行了研究 在原发性胆汁淤积患者的肝脏样本中形成。 2）定义FXR的功能和机制 FGF15 和 BA 激活的 Src 在 BA 代谢调节中的磷酸化和 3) 确定作用 FGF15 介导的 FXR 磷酸化与 PPARα 协同，终止 FGF15 信号传导。 将使用多种体外和体内方法，包括遗传和病毒生成的小鼠模型和 ChIP-seq 基因组分析可在接受 FGF19 治疗的小鼠中全面识别 FXR 结合位点。我们的专业知识 核受体的翻译后修饰和 BA 代谢的独特转录调控 使我们有资格解决 FXR 翻译后磷酸化作用这一重要的研究问题 调节 BA 代谢。我们的提案将确定 FGF15-的新功能和机制 诱导 FXR 磷酸化，并为 BA- 和 FXR 提供新的潜在治疗和诊断标记物 FGF15相关疾病，包括胆汁淤积性肝病。