Coordination of gut-liver bile acid signaling by FXR

FXR 协调肠-肝胆汁酸信号传导

• 批准号: 8849439
• 负责人: Jongsook Kim Kemper
• 金额: $ 32.29万
• 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 2017-04-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8849439
• 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; 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; Untranslated RNA; 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.

描述（由申请人提供）：本项目的总体目标是确定核胆汁酸受体，法尼醇X受体（FXR）是否通过协调肝脏和肠道对胆汁酸信号传导的反应而作为主代谢调节剂发挥作用 in vivo.胆汁酸是控制代谢和能量平衡的重要整合信号分子，FXR作为胆汁酸的主要生物传感器，通过调节基因表达在控制胆汁酸、胆固醇和葡萄糖水平中发挥重要作用。后 胆汁酸激活的FXR诱导最近鉴定的肠激素成纤维细胞生长因子19（FGF 19）的合成和分泌，其作用于肝脏以控制进食状态的代谢。β-Klotho（bKL）是FGF 19的膜共受体，因此对肝脏中的FGF 19信号传导至关重要。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转录后抑制miR-34 a来调节FGF 19信号通路基因（特别是bKL）的肝脏表达。在FXR敲除小鼠中，bKL的mRNA和蛋白水平显著降低，而miR-34 a水平升高。此外，miR-34 a可能通过直接结合bKL mRNA的3 'UTR靶向bKL。值得注意的是，在肥胖小鼠中，肝脏bKL水平显著降低，miR-34 a水平升高，并且FGF 19激活的ERK信号传导有缺陷。因此，我们假设FXR通过转录调节FGF 19途径的关键组分（特别是bKL）的表达以及通过miR-34 a抑制间接转录后上调bKL，启动肝脏通过肠道FGF 19进行信号传导。此外，肥胖症中异常的FXR/miR-34 a/bKL调节轴导致缺陷的FGF 19信号传导和异常的代谢应答。为了验证这些假设，我们将采用多种方法，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缺失小鼠的体内研究。我们将首先询问FXR是否转录调节FGF 19信号传导的关键组分（特别是bKL）的肝脏表达，并因此引发肝脏对FGF 19信号传导的响应。其次，我们将询问已知受FXR负调控的miR-34 a是否直接靶向并调节bKL的水平。我们还将研究肥胖小鼠中FXR/miR-34 a/bKL调控通路是否异常，如果是，靶向该通路的组分，特别是异常升高的miR-34，是否可能用于治疗代谢性疾病。我们提出的研究将为FXR协调肠道-肝脏胆汁酸信号传导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。