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Cited by 135Retinoids in leukemia and cellular processesRetinal Development and DisordersDrug Transport and Resistance Mechanisms

STRA6 is critical for cellular Vitamin A uptake and homeostasis

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Amengual, Jaume, Zhang, Ning, Kemerer, Mary, Maeda, Tadao, Palczewski, Krzysztof, Von Lintig, Johannes·2014·Human Molecular Genetics
DOI 10.1093/hmg/ddu258PMC PMC4168826
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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.

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  • The results in RPE-DKO mice phenocopy some phenotypes observed for Stra6−/− mice, including low retinoid content, lack of an ERG response, decreases of BM and RPE lengths, and altered morphology of RPE cells.

    “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]

    The 'STRA6 is required for eye development and function' section reports sevenfold lower ocular retinoids, reduced RPE cell sizes, and altered RPE morphology in Stra6-null mice. It says ERG responses were markedly diminished, not absent. Figure 5 describes reduced RPE in the affected area, but our copy does not report decreases in BM and RPE lengths. (LLM, conf=0.88)

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  • STRA6 is the primary retinol transporter from the blood into the RPE and during development.

    “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]

    The ‘Vitamin A transports across the CP and RPE’ section says STRA6 is critical for vitamin A transport across the RPE blood–tissue barrier, and ‘STRA6 is required for eye development and function’ links it to vitamin A homeostasis in developing eyes. But the paper establishes that STRA6-mediated uptake is mandatory when RBP4 is the only transport mode during vitamin A deficiency; it does not establish STRA6 as the primary transporter under all conditions or specifically quantify its primacy during development. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Delivery of RBP-bound vitamin A to specific tissues is mediated by a RBP receptor called STRA6.

    “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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Authors
Amengual, J., Zhang, N., Kemerer, M., Maeda, T., Palczewski, K., & Von Lintig, J.
Affiliations
Case Western Reserve University (US)
Corresponding author
Palczewski, Krzysztof
ORCID
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
DOI
10.1093/hmg/ddu258
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
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
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › 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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