视黄醇(retinol)是维持机体的正常生长发育所必需的物质,其代谢的产物通过与相关受体结合影响相关基因的转录而发挥作用。人体所需的视黄醇大部分来源于饮食中的维生素A,细胞以全视黄醇结合蛋白(holo-RBP4)循环形式摄入维生素A,这是一种自我稳定过程,而这一过程明显的依赖于多区域细胞膜蛋白STRA6。有研究表明,STRA6是维生素A进入细胞内部的关键因素。在人类中,STRA6的变异与Matthew-Wood综合症有关,这是一种遗传性疾病,其临床表现主要为多个系统的发育畸形。
在2008年3月5日出版的《细胞—代谢》(Cell Metabolism)上,来自德国和美国的一组科学家表示,他们发现了Matthew-Wood综合症的代谢基础。在研究中科学家们发现,在培养的NIH 3T3纤维原细胞中,视黄醇从RBP4向细胞内的转移过程能够被卵磷脂视黄醇酰基转移酶(lecithin:retinol acyltransferase LRAT)大大增强,这一过程与STRA6相关。
视黄醇转移是一个双向过程,这表明STRA6的作用很可能是视黄醇的输送通道或是运输因子。通过对斑马鱼胚胎的缺失功能分析,研究人员发现STRA6的不足会造成发育中眼睛的维生素A缺失。文章还表示,在缺乏STRA6的情况下,holo-Rbp4会诱发多个胚胎组织中非特异性维生素A的过剩,并损伤视黄酸受体信号以及基因调控。而STRA6缺乏所导致的致命结果,例如颅面、心脏缺陷以及眼部发育不良(microphthalmia)能通过降低胚胎中RBP4的浓度得到大大改观,降低RBP4可通过吗啉代低聚核苷酸(morpholino oligonucleotide)或者药理学治疗实现。(科学网 何宏辉/编译)
生物谷推荐原始出处:
(Cell Metabolism),Vol 7, 258-268, 05 March 2008,Andrea Isken, Johannes von Lintig
RBP4 Disrupts Vitamin A Uptake Homeostasis in a STRA6-Deficient Animal Model for Matthew-Wood Syndrome
Andrea Isken,1 Marcin Golczak,2 Vitus Oberhauser,1 Silke Hunzelmann,1,2 Wolfgang Driever,1 Yoshikazu Imanishi,2 Krzysztof Palczewski,2, and Johannes von Lintig1,2,
1 Institut für Biologie 1, Albert-Ludwigs-Universität Freiburg, 79104 Freiburg, Germany
2 Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, OH 44106-4965, USA
Summary
The cellular uptake of vitamin A from its RBP4-bound circulating form (holo-RBP4) is a homeostatic process that evidently depends on the multidomain membrane protein STRA6. In humans, mutations in STRA6 are associated with Matthew-Wood syndrome, manifested by multisystem developmental malformations. Here we addressed the metabolic basis of this inherited disease. STRA6-dependent transfer of retinol from RBP4 into cultured NIH 3T3 fibroblasts was enhanced by lecithin:retinol acyltransferase (LRAT). The retinol transfer was bidirectional, strongly suggesting that STRA6 acts as a retinol channel/transporter. Loss-of-function analysis in zebrafish embryos revealed that Stra6 deficiency caused vitamin A deprivation of the developing eyes. We provide evidence that, in the absence of Stra6, holo-Rbp4 provokes nonspecific vitamin A excess in several embryonic tissues, impairing retinoic acid receptor signaling and gene regulation. These fatal consequences of Stra6 deficiency, including craniofacial and cardiac defects and microphthalmia, were largely alleviated by reducing embryonic Rbp4 levels by morpholino oligonucleotide or pharmacological treatments