• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文学位 >Novel human Constitutive Androstane Receptor Activators and their Effects on Hepatic Energy Homeostasis.
【24h】

Novel human Constitutive Androstane Receptor Activators and their Effects on Hepatic Energy Homeostasis.

机译：新型人类组成型雄激素受体激活剂及其对肝能量稳态的影响。

获取原文
获取原文并翻译 | 示例
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

The constitutive androstane receptor (CAR, NR1I3) serves as a ligand-activated transcription factor transforming chemical stimuli into cellular responses by regulating the expression of its target genes. CAR is well-recognized as a key mediator affecting drug metabolism and transport in response to a broad range of xenobiotics. It is predominantly expressed in the liver and intestine; where it regulates the inductive expression of phase I and II drug metabolizing enzyme target genes such as cytochrome P450 (CYP) 2B6, CYP3A4, sulfotransferases, and glutathione s-transferases, and drug transporters such as multidrug resistance protein 1 and organic anion-transporting polypeptides. Recent animal studies revealed that CAR also influences gluconeogenesis, lipogenesis, and fatty acid synthesis, and potentially ameliorates diabetes and obesity. Thus, discovery of compounds activating or deactivating CAR offers a promising avenue for the prediction of induction-mediated drug-drug interactions and a potential therapeutic strategy for metabolic diseases.;Strategies incorporating computational based virtual screening with biological approaches were employed to identify and validate novel human (h) CAR modulators. Luciferase reporter assays were performed by transfecting various hCAR expression and CYP2B6 reporter plasmids into HepG2 cells. A stable cell line expressing both CYP2B6 luciferase and hCAR vectors was generated to identify novel hCAR activators and deactivators in a high-throughput manner. Human primary hepatocytes were utilized to explore the effects of CAR activation on target gene expression and hepatic energy homeostasis.;Overall, this project revealed that a combined computational and biological approach is effective for identifying hCAR activators. The novel double stable cell line generated here offers a unique cell model in identification of both hCAR agonists and antagonists at high-throughput levels. The most distinctive finding obtained through this research however, was the species difference between hCAR and mouse (m) CAR energy metabolism. Activation of mCAR represses the expression of genes associated with gluconeogenesis, lipogenesis, and fatty acid synthesis, while activation of hCAR selectively inhibits gluconeogenesis without suppressing fatty acid synthesis. These findings warrant caution with respect to the interpretation and extrapolation of results obtained from animal models to humans.
机译：组成型雄甾烷受体（CAR，NR1I3）用作配体激活的转录因子，通过调节其靶基因的表达将化学刺激转化为细胞反应。 CAR被公认为是影响药物对多种异源生物的代谢和转运的关键介质。它主要在肝和肠中表达；它调节I和II期药物代谢酶靶基因的诱导表达，例如细胞色素P450（CYP）2B6，CYP3A4，磺基转移酶和谷胱甘肽S-转移酶，以及药物转运蛋白，例如多药耐药蛋白1和有机阴离子转运多肽。最近的动物研究表明，CAR还影响糖异生，脂肪生成和脂肪酸合成，并可能改善糖尿病和肥胖症。因此，发现激活或失活CAR的化合物为预测诱导介导的药物相互作用提供了一种有希望的途径，并且为代谢性疾病提供了潜在的治疗策略。；采用基于计算的虚拟筛选与生物学方法相结合的策略来鉴定和验证新型人类（h）CAR调节剂。通过将各种hCAR表达和CYP2B6报告质粒转染到HepG2细胞中，进行了荧光素酶报告基因检测。产生表达CYP2B6荧光素酶和hCAR载体的稳定细胞系，以高通量的方式鉴定新型hCAR激活剂和去激活剂。利用人类原代肝细胞来探索CAR激活对靶基因表达和肝能量稳态的影响。总体而言，该项目表明，结合计算和生物学方法可有效鉴定hCAR激活剂。在此生成的新型双稳定细胞系为高通量水平的hCAR激动剂和拮抗剂的鉴定提供了独特的细胞模型。通过这项研究获得的最独特发现是hCAR和小鼠（m）CAR能量代谢之间的物种差异。 mCAR的激活会抑制与糖异生，脂肪生成和脂肪酸合成相关的基因的表达，而hCAR的激活选择性地抑制糖异生而不会抑制脂肪酸的合成。对于从动物模型获得的结果的解释和外推，这些发现值得谨慎。

著录项

  • 作者

    Lynch, Caitlin.;

  • 作者单位

    University of Maryland, Baltimore.;

  • 授予单位 University of Maryland, Baltimore.;
  • 学科 Health Sciences Pharmacy.
  • 学位 Ph.D.
  • 年度 2014
  • 页码 167 p.
  • 总页数 167
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 地球物理学;
  • 关键词

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号