Coordination of gut-liver bile acid signaling by FXR

FXR 协调肠-肝胆汁酸信号传导

• 批准号: 8492085
• 负责人: Jongsook Kim Kemper
• 金额: $ 30.42万
• 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/8492085
• 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.

描述（由申请人提供）：该项目的总体目标是确定核胆汁酸受体 Farnesoid 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来发挥主要代谢调节剂的作用 体内。胆汁酸是控制代谢和能量平衡的重要综合信号分子，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方面发挥着重要作用。后 进餐时，胆汁酸激活的 FXR 会诱导最近发现的肠道激素——成纤维细胞生长因子 19 (FGF19) 的合成和分泌，该激素作用于肝脏，控制进食状态下的代谢。 Beta-Klotho (bKL) 是 FGF19 的膜辅助受体，因此对于肝脏中的 FGF19 信号转导至关重要。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通过抑制 miR-34a 进行转录后调节 FGF19 信号通路基因的肝脏表达，特别是 bKL。在 FXR 缺失小鼠中，bKL 的 mRNA 和蛋白水平显着降低，而 miR-34a 水平则升高。此外，miR-34a 可能通过直接结合 bKL mRNA 的 3'UTR 来靶向 bKL。值得注意的是，在肥胖小鼠中，肝脏 bKL 水平大幅降低，miR-34a 水平升高，并且 FGF19 激活的 ERK 信号传导存在缺陷。因此，我们假设 FXR 通过转录调节 FGF19 通路关键成分（特别是 bKL）的表达以及通过抑制 miR-34a 间接上调转录后 bKL 来启动肝脏接收肠道 FGF19 信号传导。此外，肥胖中异常的 FXR/miR-34a/bKL 调节轴会导致 FGF19 信号传导缺陷和代谢反应异常。为了检验这些假设，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。我们首先要问的是，FXR 是否在转录上调节 FGF19 信号传导关键成分（尤其是 bKL）的肝脏表达，从而启动肝脏对 FGF19 信号传导做出反应。其次，我们要问的是，已知受到 FXR 负向调节的 miR-34a 是否直接靶向并调节 bKL 水平。我们还将检查肥胖小鼠中的 FXR/miR-34a/bKL 调节通路是否异常，如果是，则针对该通路的成分（特别是异常升高的 miR-34）是否可能有助于治疗代谢疾病。我们提出的研究应该为 FXR 协调肠肝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。