STRA6 is critical for cellular vitamin A uptake and homeostasis.
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.
Department of Pharmacology, School of Medicine.
Jaume
J
Amengual
Department of Pharmacology, School of Medicine.
Ning
N
Zhang
Department of Pharmacology, School of Medicine.
Mary
M
Kemerer
Department of Pharmacology, School of Medicine, Department of Ophthalmology, School of Medicine.
Tadao
T
Maeda
Department of Pharmacology, School of Medicine, Cleveland Center for Membrane and Structural Biology, Case Western Reserve University, Cleveland, OH 44106, USA kxp65@case.edu jxv99@case.edu.
Krzysztof
K
Palczewski
Department of Pharmacology, School of Medicine, kxp65@case.edu jxv99@case.edu.
Johannes
J
Von Lintig
D000818:Animals; D001921:Brain / Q000378:metabolism; D002831:Choroid Plexus / Q000378:metabolism; D005123:Eye / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D006706:Homeostasis; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D021381:Protein Transport; D012176:Retinoids / Q000378:metabolism; D054839:Retinol-Binding Proteins, Plasma / Q000378:metabolism; D014801:Vitamin A / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014802:Vitamin A Deficiency / Q000178:diet therapy / Q000235:genetics
D008565:Membrane Proteins; C502487:Rbp4 protein, mouse; D012176:Retinoids; D054839:Retinol-Binding Proteins, Plasma; C108001:Stra6 protein, mouse; D014801:Vitamin A