Zhu Jingmin, Hu Lingling, Li Lingyun, Huang Xiao, Shi Huahong
State Key Laboratory of Estuarine and Coastal Research, East China Normal University, Shanghai 200062, China.
Institute of Cellular and Developmental Biology, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, China.
Toxicol Appl Pharmacol. 2017 Sep 1;330:40-47. doi: 10.1016/j.taap.2017.07.004. Epub 2017 Jul 6.
Retinoic acid functions through two classes of receptors, i.e., the retinoic acid receptor (RAR) and the retinoid X receptor (RXR). The difference in the role between RAR and RXR, however, are not well clarified. In the present study, we comparatively investigated the phenotypic and global gene expression changes in Xenopus tropicalis embryos induced by three different agonists, including a RAR selective ligand (all-trans retinoic acid, at-RA), a RXR selective ligand (fluorobexarotene, FBA) and their common ligand (9-cis retinoic acid, 9c-RA). All three agonists induced striking and similar malformations in X. tropicalis embryos at the concentrations of 5-50μg/L. Especially, the development of anterior structures and caudal region was dramatically altered. The hierarchical clustering analysis of phenotypes and gene profiles suggested that effects induced by 9c-RA separated from those by at-RA and FBA. The up-regulated genes were involved in multiple pathways while down-regulated genes were mainly related to phototransduction and tyrosine metabolism. at-RA primarily affected the retinol, glycolysis, starch and sucrose metabolisms while FBA led to disturbances in more wide-ranging pathways such as the PPAR, adipocytokine, insulin, FoxO signaling pathways, alanine, aspartate and glutamate metabolism. RXR is a heterodimeric partner for several other nuclear receptors, which opens the possibility that additional retinoid effects could be mediated by FBA, such as RXR-PPAR. Our data indicates that not only RXR-RAR but also RXR-PPAR plays important roles in the control of metabolism with retinoid treatment in X. tropicalis embryos.
视黄酸通过两类受体发挥作用，即视黄酸受体（RAR）和类视黄醇X受体（RXR）。然而，RAR和RXR之间作用的差异尚未得到很好的阐明。在本研究中，我们比较研究了三种不同激动剂诱导的热带爪蟾胚胎的表型和全局基因表达变化，这三种激动剂包括一种RAR选择性配体（全反式视黄酸，at-RA）、一种RXR选择性配体（氟维司群，FBA）及其共同配体（9-顺式视黄酸，9c-RA）。在5-50μg/L的浓度下，所有三种激动剂均在热带爪蟾胚胎中诱导出显著且相似的畸形。特别是，前部结构和尾部区域的发育发生了显著改变。表型和基因图谱的层次聚类分析表明，9c-RA诱导的效应与at-RA和FBA诱导的效应不同。上调基因涉及多个途径，而下调基因主要与光转导和酪氨酸代谢有关。at-RA主要影响视黄醇、糖酵解、淀粉和蔗糖代谢，而FBA导致更广泛途径的紊乱，如PPAR、脂肪细胞因子、胰岛素、FoxO信号通路、丙氨酸、天冬氨酸和谷氨酸代谢。RXR是其他几种核受体的异二聚体伴侣，这使得FBA可能介导额外的类视黄醇效应，如RXR-PPAR。我们的数据表明，在热带爪蟾胚胎中，不仅RXR-RAR而且RXR-PPAR在类视黄醇处理对代谢的控制中都起着重要作用。
