Impaired retinal function and vitamin A availability in mice lacking retinol-binding protein
Impaired retinal function and vitamin A availability in mice lacking retinol-binding protein
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DOI：
10.1093/emboj/18.17.4633
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发表时间：
1999-09-01
期刊：
影响因子：
11.4
通讯作者：
Gottesman, ME
中科院分区：
文献类型：
--
作者：
Quadro, L;Blaner, WS;Gottesman, ME
视黄醇结合蛋白 (RBP) 是循环中视黄醇（维生素 A）的唯一特异性转运蛋白，其唯一已知功能是将视黄醇递送至组织。在组织内，视黄醇被激活为视黄酸，视黄酸与核受体结合，调节超过 300 个不同靶基因的转录。在眼睛中，视黄醇也被激活为 11-顺式视黄醛（视觉发色团）。我们通过基因打靶生成了 REP 敲除小鼠 (RBP-/-)。这些小鼠有几种表型。尽管具有活力和生育能力，但它们在生命的最初几个月内血液视黄醇水平降低，视网膜功能明显受损。这种损害不是由于发育性视网膜缺陷造成的。给予充足维生素 A 的饮食，RBP-/- 小鼠在 5 个月大时即可获得正常视力，即使血液视黄醇水平仍然较低。如果缺乏膳食维生素 A，视力仍然异常，并且血液视黄醇降至不可检测的水平。突变小鼠的另一个显着表型是其异常的视黄醇代谢。 RBP-/-小鼠可以获得肝脏视黄醇储存，但这些储存不能被动员。因此，它们的维生素 A 状态极其微弱，并且依赖于定期维生素 A 摄入量。与野生型小鼠不同，成年 RBP-/- 动物的血清视黄醇水平在缺乏维生素 A 的饮食仅一周后就检测不到，并且它们的视网膜功能迅速恶化。因此，幼小动物的正常视力和在饮食摄入不足时视黄醇的动员需要 REP，但对于将视黄醇输送到组织而言，REP 是可有可无的。
Retinol-binding protein (RBP) is the sole specific transport protein for retinol (vitamin A) in the circulation, and its single known function is to deliver retinol to tissues. Within tissues, retinol is activated to retinoic acid, which binds to nuclear receptors to regulate transcription of >300 diverse target genes. In the eye, retinol is also activated to 11-cis-retinal, the visual chromophore, We generated REP knockout mice (RBP-/-) by gene targeting. These mice have several phenotypes. Although viable and fertile, they have reduced blood retinol levels and markedly impaired retinal function during the first months of life. The impairment is not due to developmental retinal defect. Given a vitamin A-sufficient diet, the RBP-/- mice acquire normal vision by 5 months of age even though blood retinol levels remain low, Deprived of dietary vitamin A, vision remains abnormal and blood retinol declines to undetectable levels. Another striking phenotype of the mutant mice is their abnormal retinol metabolism. The RBP-/- mice can acquire hepatic retinol stores, but these cannot be mobilized. Thus, their vitamin A status is extremely tenuous and dependent on a regular vitamin A intake, Unlike wild-type mice, serum retinol levels in adult RBP-/- animals become undetectable after only a week on a vitamin A-deficient diet and their retinal function rapidly deteriorates, Thus REP is needed for normal vision in young animals and for retinol mobilization in times of insufficient dietary intake, but is otherwise dispensable for the delivery of retinol to tissues.