Exposure to the synthetic FXR agonist GW4064 causes alterations in gene expression and sublethal hepatotoxicity in eleutheroembryo medaka (Oryzias latipes).
Exposure to the synthetic FXR agonist GW4064 causes alterations in gene expression and sublethal hepatotoxicity in eleutheroembryo medaka (Oryzias latipes).
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DOI：
10.1016/j.taap.2009.11.022
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发表时间：
2010-02-15
影响因子：
3.8
通讯作者：
Hinton DE
中科院分区：
文献类型：
--
作者：
Howarth DL;Law SH;Law JM;Mondon JA;Kullman SW;Hinton DE
青鳉（Oryzias latipes）是一种小型淡水硬骨鱼，在肝脏和胆道系统慢性毒性研究中有着广泛的应用历史。该模型的最新进展集中在定义青鳉肝胆系统。在此，我们通过检测法尼醇X受体α（FXRα，NR1H4）的体内作用和功能来研究关键肝功能和毒性，FXR α是核受体超家族的一员，在胆汁酸稳态调节中起着重要作用。对青鳉FXRα mRNA的定量分析表明，在含有剩余卵黄的自由游动青鳉胚胎（eleutheroembryos，EEs）和成体中，FXRα的两种亚型Fxrα1和Fxrα2的表达存在差异。使用GW4064（一种强FXRα激动剂）在体内激活青鳉Fxrα，导致定义的FXRα基因靶点（包括胆盐输出蛋白、小异源二聚体伴侣和细胞色素P450 7A1）的基因表达改变。暴露于GW 4064后青鳉肝脏的组织学检查显示，肝脏的肝细胞和胆管上皮细胞中存在显著的脂质蓄积、细胞和细胞器改变。这份报告的肝胆损伤后，GW 4064暴露扩展了以前的调查，在青鳉肝内胆道系统，揭示了敏感性毒物暴露，并说明需要增加分辨率在检测和解释的毒性反应，在这种脊椎动物。
The small freshwater teleost, medaka (Oryzias latipes), has a history of usage in studies of chronic toxicity of liver and biliary system. Recent progress with this model has focused on defining the medaka hepatobiliary system. Here we investigate critical liver function and toxicity by examining the in vivo role and function of the farnesoid X receptor alpha (FXRα, NR1H4), a member of the nuclear receptor superfamily that plays an essential role in the regulation of bile acid homeostasis. Quantitative mRNA analysis of medaka FXRα demonstrates differential expression of two FXRα isoforms designated Fxrα1 and Fxrα2, in both free swimming medaka embryos with remaining yolk (eleutheroembryos, EEs) and adults. Activation of medaka Fxrα in vivo with GW4064 (a strong FXRα agonist) resulted in modification of gene expression for defined FXRα gene targets including the bile salt export protein, small heterodimer partner, and cytochrome P450 7A1. Histological examination of medaka liver subsequent to GW4064 exposure demonstrated significant lipid accumulation, cellular and organelle alterations in both hepatocytes and biliary epithelial cells of the liver. This report of hepatobiliary injury following GW4064 exposure extends previous investigations of the intrahepatic biliary system in medaka, reveals sensitivity to toxicant exposure, and illustrates the need for added resolution in detection and interpretation of toxic responses in this vertebrate.
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DOI：
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发表时间：
2009-03-01
影响因子：
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