Amengual Jaume, Zhang Ning, Kemerer Mary, Maeda Tadao, Palczewski Krzysztof, Von Lintig Johannes
Department of Pharmacology, School of Medicine.
Department of Pharmacology, School of Medicine, Department of Ophthalmology, School of Medicine.
Hum Mol Genet. 2014 Oct 15;23(20):5402-17. doi: 10.1093/hmg/ddu258. Epub 2014 May 22.
Vitamin A must be adequately distributed within the body to maintain the functions of retinoids in the periphery and chromophore production in the eyes. Blood transport of the lipophilic vitamin is mediated by the retinol-binding protein, RBP4. Biochemical evidence suggests that cellular uptake of vitamin A from RBP4 is facilitated by a membrane receptor. This receptor, identified as the Stimulated by retinoic acid gene 6 (Stra6) gene product, is highly expressed in epithelia that constitute blood-tissue barriers. Here we established a Stra6 knockout mouse model to analyze the metabolic basis of vitamin A homeostasis in peripheral tissues. These mice were viable when bred on diets replete in vitamin A, but evidenced markedly reduced levels of ocular retinoids. Ophthalmic imaging and histology revealed malformations in the choroid and retinal pigmented epithelium, early cone photoreceptor cell death, and reduced lengths of rod outer segments. Similar to the blood-retina barrier in the RPE, vitamin A transport through the blood-cerebrospinal fluid barrier in the brain's choroid plexus was impaired. Notably, treatment with pharmacological doses of vitamin A restored vitamin A transport across these barriers and rescued the vision of Stra6(-/-) mice. Furthermore, under conditions mimicking vitamin A excess and deficiency, our analyses revealed that STRA6-mediated vitamin A uptake is a regulated process mandatory for ocular vitamin A uptake when RBP4 constitutes the only transport mode in vitamin A deficiency. These findings identifying STRA6 as a bona fide vitamin A transporter have important implications for disease states associated with impaired blood vitamin A homeostasis.
维生素A必须在体内充分分布，以维持外周类视黄醇的功能以及眼睛中发色团的生成。亲脂性维生素的血液运输由视黄醇结合蛋白RBP4介导。生化证据表明，一种膜受体促进了细胞从RBP4摄取维生素A。这种受体被鉴定为视黄酸刺激基因6（Stra6）的基因产物，在构成血液-组织屏障的上皮细胞中高度表达。在这里，我们建立了一个Stra6基因敲除小鼠模型，以分析外周组织中维生素A稳态的代谢基础。这些小鼠在富含维生素A的饮食中繁殖时能够存活，但眼部类视黄醇水平明显降低。眼科成像和组织学检查显示脉络膜和视网膜色素上皮畸形、早期视锥光感受器细胞死亡以及视杆细胞外段长度缩短。与视网膜色素上皮中的血-视网膜屏障类似，大脑脉络丛中维生素A通过血-脑脊液屏障的运输也受到损害。值得注意的是，用药理剂量的维生素A进行治疗可恢复维生素A跨这些屏障的运输，并挽救Stra6（-/-）小鼠的视力。此外，在模拟维生素A过量和缺乏的条件下，我们的分析表明，当RBP4是维生素A缺乏时唯一的运输模式时，STRA6介导的维生素A摄取是眼部摄取维生素A所必需的一个受调节的过程。这些将STRA6鉴定为真正的维生素A转运蛋白的发现，对于与血液中维生素A稳态受损相关的疾病状态具有重要意义。
