STRA6 is critical for cellular vitamin A uptake and homeostasis

Abstract

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.

Retinoids and Retinal Diseases

“…This disease, typically lethal in early childhood, is characterized by a range of developmental abnormalities, including anophthalmia or microphthalmia; heart, lung, and urogenital malformations; short stature; and facial dysmorphism. Similar malformations have been observed in a STRA6 knockdown zebrafish model of Matthew-Wood syndrome (Isken et al 2008), whereas Stra6 −/− mice exhibit a more mild and restricted phenotype, primarily affecting the eye (Amengual et al 2014, Ruiz et al 2012). Dominant negative mutations in RBP4 that enhance STRA6–apo-RBP4 binding affinity have also been linked to congenital eye malformations (Chou et al 2015).…”

An Alternative Retinoic Acid-responsive Stra6 Promoter Regulated in Response to Retinol Deficiency

“…Several STRA6 mutations associated with human disease have been shown to limit or abolish retinol uptake into cells (23,24). Three groups have independently reported marked ocular defects in Stra6 null mice (25)(26)(27). Genetic ablation of Stra6 results in a reduced retinoid content in the retinal pigment epithelium and neurosensory retina (greater than a 95% reduction in retinyl esters) with consequently fewer cone photoreceptor cells and diminished cone b-wave amplitude (25).…”

“…Under vitamin A-deficient conditions, Stra6 was reported to facilitate redistribution from storage tissue (e.g. liver and lungs) to the eye (27), possibly in conjunction with the recently identified RBPR2, another RBP4 receptor (4). Ablation of Stra6 can also protect animals from the insulin-resistant state induced by feeding a high fat, high sucrose diet (28), which may be a result of impaired Jak/Stat signaling (29).…”

“…Ablation of Stra6 can also protect animals from the insulin-resistant state induced by feeding a high fat, high sucrose diet (28), which may be a result of impaired Jak/Stat signaling (29). Why humans with certain mutations in STRA6 exhibit a more severe morphological phenotype (25)(26)(27) than the Stra6 knock-out mice is currently not understood.…”

Structure of the STRA6 receptor for retinol uptake

“…Consistent with an important role of STRA6 in maintaining vitamin A homoeostasis in the eye, a zebrafish stra6 gene knockdown model also exhibited severe ocular malformations during development (24). Stra6 knockout mice have a less severe phenotype, exhibiting defects in the visual cycle (25, 26) and impaired insulin signaling (27). …”