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STRA6 is critical for cellular vitamin A uptake and homeostasis
Open accessAbstract
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.
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“These results phenocopy some of the phenotypes observed for Stra6 −/− mice, including low retinoid content, the lack of an ERG response, decreases of BM and RPE lengths, and altered morphology of RPE cells ( 53 ).”
From Loss of Extracellular Signal-Regulated Kinase 1/2 in the Retinal Pigment Epithelium Leads to RPE65 Decrease and Retinal Degeneration (2017) · cites this paper as [53]
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“Their research in 2014 established STRA6 as the primary retinol transporter from the blood into the RPE and during development, and that vitamin A deficient mutant mice exhibited diseased phenotypes as previous studies, which were rescued to normal visual function by treatments of retinoid doses [38].”
From Vitamin A Transporters in Visual Function: A Mini Review on Membrane Receptors for Dietary Vitamin A Uptake, Storage, and Transport to the Eye (2021) · cites this paper as [38]
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“Delivery of RBP bound vitamin A to specific tissues is mediated by a RBP receptor called STRA6 (stimulated by retinoic acid 6) (Figure 2) [69,70,71].”
From Molecular Basis for Vitamin A Uptake and Storage in Vertebrates (2016) · cites this paper as [71]
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Metadata
- Authors
- Amengual, J., Zhang, N., Kemerer, M., Maeda, T., Palczewski, K., & Von Lintig, J.
- Affiliations
- Case Western Reserve University (US)
- Corresponding author
- Palczewski, Krzysztof
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2014-05-22
- Volume
- 23
- Issue
- 20
- Pages
- 5402-5417
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC4168826
- OpenAlex
- W2129235226
- Cited by
- 134
- References
- 69
- Citations by year
- 2026: 6 · 2025: 16 · 2024: 16 · 2023: 12 · 2022: 11 · 2021: 9 · 2020: 15 · 2019: 14 · 2018: 3 · 2017: 7 · 2016: 10 · 2015: 12 · 2014: 3
- FWCI
- 4.37
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Case Western Reserve University
- National Eye Institute (EY020551, EY019641, R01EY019641, R01EY020551)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Health Sciences › Medicine › Ophthalmology › Retinal Development and Disorders
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- STRA6, vitamin A homeostasis, retinol-binding protein 4, choroid, retinal pigment epithelium, photoreceptor cell death, choroid plexus, blood-CSF barrier, blood-retinal barrier, vitamin A deficiency, vitamin A excess, knockout mouse models
- MeSH terms
- Animals, Brain, Choroid Plexus, Eye, Homeostasis, Membrane Proteins, Mutation, Retinoids, Vitamin A, Vitamin A Deficiency, Mice, Knockout, Protein Transport, Mice, Retinol-Binding Proteins, Plasma
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