STRA6 is critical for cellular vitamin A uptake and homeostasis
STRA6 is critical for cellular vitamin A uptake and homeostasis
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DOI：
10.1093/hmg/ddu258
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发表时间：
2014-10-15
影响因子：
3.5
通讯作者：
Von Lintig, Johannes
中科院分区：
文献类型：
--
作者：
Amengual, Jaume;Zhang, Ning;Von Lintig, Johannes
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和眼睛中生色团的产生。亲脂性维生素的血液运输是由视黄醇结合蛋白 RBP4 介导的。生化证据表明，细胞从 RBP4 中摄取维生素 A 是由膜受体促进的。这种受体被确定为视黄酸刺激基因 6 (Stra6) 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Stra6基因敲除小鼠模型来分析外周组织中维生素A稳态的代谢基础。这些小鼠在食用富含维生素 A 的饮食后仍能存活，但证据表明眼部类视黄醇水平显着降低。眼科成像和组织学显示脉络膜和视网膜色素上皮畸形、早期视锥细胞死亡以及视杆外节长度缩短。与 RPE 中的血-视网膜屏障类似，维生素 A 通过大脑脉络丛中的血-脑脊液屏障的转运也受到损害。值得注意的是，用药物剂量的维生素 A 治疗可以恢复维生素 A 跨过这些屏障的转运，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 构成维生素 A 缺乏症的唯一转运模式时，STRA6 介导的维生素 A 摄取是眼部维生素 A 摄取的强制性调节过程。这些发现将 STRA6 确定为真正的维生素 A 转运蛋白，对于与血液维生素 A 稳态受损相关的疾病状态具有重要意义。
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.