Coordination of gut-liver bile acid signaling by FXR

FXR 协调肠-肝胆汁酸信号传导

• 批准号: 8344054
• 负责人: Jongsook Kim Kemper
• 金额: $ 31.01万
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8344054
• 关键词: 3' Untranslated Regions; Agonist; Amino Acids; Bile Acids; Binding; Binding Sites; Biological Assay; Biosensor; Cell Culture Techniques; Cells; Cholesterol; Complex; Data; Disease; Down-Regulation; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Functional RNA; Gene Expression; Gene Expression Regulation; Genes; Glucose; Goals; Hepatic; Hepatocyte; Hormones; In Vitro; Intestinal Hormones; Intestines; Knockout Mice; Ligands; Lipids; Liver; Mediating; Membrane; Messenger RNA; Metabolic; Metabolic Diseases; Metabolism; MicroRNAs; Mus; Nuclear; Nuclear Receptors; Obese Mice; Obesity; Pancreas; Pathway interactions; Pattern; Physiology; Play; Proteins; Ras/Raf; Regulatory Pathway; Reporter; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Signaling Pathway Gene; Testing; Therapeutic; Transcriptional Regulation; adenoviral-mediated; base; chromatin immunoprecipitation; energy balance; farnesoid X-activated receptor; feeding; genome-wide; genome-wide analysis; improved; in vivo; insight; new therapeutic target; novel; overexpression; receptor; receptor binding; receptor function; research study; response; sugar

DESCRIPTION (provided by applicant): The overall goal of this project is to determine whether the nuclear bile acid receptor, Farnesoid X Receptor (FXR), functions as a master metabolic regulator by coordinating the responses of the liver and intestine to bile acid signaling in vivo. Bile acids are important integrative signaling molecules that control metabolism and energy balance and FXR, as the primary biosensor for bile acids, plays an important role in controlling bile acid, cholesterol, and glucose levels through regulation of gene expression. After a meal, bile acid-activated FXR induces the synthesis and secretion of a recently identified intestinal hormone, fibroblast growth factor 19 (FGF19), which acts at the liver to control fed-state metabolism. Beta-Klotho (bKL) is the membrane coreceptor for FGF19 and, thus, is crucial for the FGF19 signaling in the liver. Our recent genome-wide hepatic FXR binding and microRNA (miR) studies have suggested that FXR may regulate hepatic expression of FGF19 signaling pathway genes, particularly bKL, both by induction of gene expression and post-transcriptionally through the inhibition of miR-34a. In FXR null mice, the mRNA and protein levels of bKL were substantially decreased, whereas miR-34a levels were increased. Moreover, miR-34a likely targets bKL by directly binding to the 3'UTR of the bKL mRNA. Remarkably, hepatic bKL levels were substantially reduced, miR-34a levels were elevated, and FGF19-activated ERK signaling was defective in obese mice. Therefore, we hypothesize that FXR primes the liver for signaling by intestinal FGF19 both by transcriptionally regulating expression of key components of the FGF19 pathway, particularly bKL, and by post-transcriptionally up-regulating bKL indirectly through miR-34a inhibition. Further, an aberrant FXR/miR-34a/bKL regulatory axis in obesity contributes to defective FGF19 signaling and abnormal metabolic responses. To test these hypotheses, we will employ multiple approaches from in vitro and cell culture, including primary hepatocytes, studies to in vivo studies using normal, obese, and FXR-null mice. We will first ask whether FXR transcriptionally regulates hepatic expression of key components of FGF19 signaling, particularly bKL, and therefore, primes the liver to respond to FGF19 signaling. Second we will ask whether miR-34a, known to be negatively regulated by FXR, directly targets and regulates the levels of bKL. We will also examine whether this FXR/miR-34a/bKL regulatory pathway is abnormal in obese mice, and, if so, whether targeting components of this pathway, particularly the aberrantly elevated miR-34, might be useful in the treatment of metabolic disease. Our proposed studies should provide new insights into the mechanisms by which FXR coordinates gut-liver bile acid signaling and may reveal novel therapeutic targets to treat metabolic disorders. PUBLIC HEALTH RELEVANCE: Farnesoid X Receptor (FXR) functions as the primary biosensor for bile acids and plays an important role in maintaining lipid and sugar levels through regulation of gene expression in the liver and intestine. After a meal, bile acid-activated FXR induces the synthesis of an intestinal hormone, fibroblast growth factor 19 (FGF19), which acts at the liver to control fed-state metabolism. We will test the novel hypotheses that FXR not only induces intestinal FGF19 synthesis but also primes the liver to respond to FGF19, by transcriptionally regulating expression of the FGF19 signaling pathway genes, particularly the FGF19 co-receptor beta-Klotho (bKL), and also by post-transcriptionally regulating bKL through the inhibition of microRNA-34a (miR-34a), and this FXR/miR-34a/bKL regulatory axis is abnormal in obesity, and that targeting the aberrantly elevated miR- 34a may be useful in the treatment of metabolic diseases.

描述(申请人提供)：本项目的总体目标是确定核胆酸受体法尼西德X受体(FXR)是否通过协调肝脏和肠道对胆汁酸信号的反应而发挥主要代谢调节作用。 在活体内。胆汁酸是控制新陈代谢和能量平衡的重要信号分子，FXR作为胆汁酸的主要生物传感器，通过基因表达调控胆汁酸、胆固醇和葡萄糖水平，发挥着重要的作用。之后 一餐，胆汁酸激活的FXR诱导合成和分泌一种新近发现的肠道激素，成纤维细胞生长因子19(FGF19)，它作用于肝脏，控制喂养状态的代谢。β-Klotho(BKL)是FGF19的膜共受体，对肝脏中的FGF19信号转导起着至关重要的作用。我们最近的全基因组肝脏FXR结合和microRNA(MiR)研究表明，FXR可能通过诱导基因表达和通过抑制miR-34a在转录后调节FGF19信号通路基因的表达，特别是BKL。在FXR基因缺失的小鼠中，BKL的mRNA和蛋白水平显著降低，而miR-34a的水平显著升高。此外，miR-34a可能通过直接与BKL基因的3‘端非编码区结合而靶向BKL。值得注意的是，肥胖小鼠的肝脏BKL水平显著降低，miR-34a水平上升，FGF19激活的ERK信号转导存在缺陷。因此，我们假设FXR通过转录调控FGF19途径关键成分的表达，特别是BKL，以及通过miR-34a抑制间接转录上调BKL，从而启动肝脏通过肠道FGF19传递信号。此外，肥胖中FXR/miR-34a/BKL调节轴的异常导致了FGF19信号的缺陷和代谢反应的异常。为了验证这些假设，我们将使用多种方法，从体外和细胞培养，包括原代肝细胞，研究到使用正常、肥胖和FXR基因缺失的小鼠的体内研究。我们将首先询问FXR是否在转录水平上调节肝脏FGF19信号的关键成分，特别是BKL的表达，从而启动肝脏对FGF19信号的反应。其次，我们将询问已知受FXR负调控的miR-34a是否直接靶向并调节BKL的水平。我们还将检查该FXR/miR-34a/BKL调控途径在肥胖小鼠中是否异常，如果是，靶向该途径的组件，特别是异常升高的miR-34，是否可能在治疗代谢性疾病方面有用。我们提出的研究将为FXR协调肠道-肝脏胆汁酸信号的机制提供新的见解，并可能揭示治疗代谢紊乱的新治疗靶点。 公共卫生相关性：法尼醇X受体(FXR)是胆汁酸的主要生物传感器，通过调节肝脏和肠道中的基因表达，在维持血脂和血糖水平方面发挥着重要作用。餐后，胆汁酸激活的FXR诱导肠道激素成纤维细胞生长因子19(FGF19)的合成，该激素作用于肝脏，控制喂养状态的新陈代谢。我们将检验新的假设，即FXR不仅诱导肠道FGF19合成，而且启动肝脏对FGF19的反应，通过转录调控FGF19信号通路基因的表达，特别是FGF19共受体β-Klotho(BKL)，以及通过抑制microRNA-34a(miR-34a)转录后调节BKL，这个FXR/miR-34a/BKL调节轴在肥胖中是异常的，针对异常升高的miR-34a可能有助于代谢性疾病的治疗。