title: RBP4 disrupts vitamin A uptake homeostasis in a STRA6-deficient animal model for Matthew-Wood syndrome.
abstract: The cellular uptake of vitamin A from its RBP4-bound circulating form (holo-RBP4) is a homeostatic process that evidently depends on the multidomain membrane protein STRA6. In humans, mutations in STRA6 are associated with Matthew-Wood syndrome, manifested by multisystem developmental malformations. Here we addressed the metabolic basis of this inherited disease. STRA6-dependent transfer of retinol from RBP4 into cultured NIH 3T3 fibroblasts was enhanced by lecithin:retinol acyltransferase (LRAT). The retinol transfer was bidirectional, strongly suggesting that STRA6 acts as a retinol channel/transporter. Loss-of-function analysis in zebrafish embryos revealed that Stra6 deficiency caused vitamin A deprivation of the developing eyes. We provide evidence that, in the absence of Stra6, holo-Rbp4 provokes nonspecific vitamin A excess in several embryonic tissues, impairing retinoic acid receptor signaling and gene regulation. These fatal consequences of Stra6 deficiency, including craniofacial and cardiac defects and microphthalmia, were largely alleviated by reducing embryonic Rbp4 levels by morpholino oligonucleotide or pharmacological treatments.
authors.affiliation: Institut für Biologie 1, Albert-Ludwigs-Universität Freiburg, 79104 Freiburg, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Isken
authors.forename: Marcin
authors.initials: M
authors.lastname: Golczak
authors.forename: Vitus
authors.initials: V
authors.lastname: Oberhauser
authors.forename: Silke
authors.initials: S
authors.lastname: Hunzelmann
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Driever
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Imanishi
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Palczewski
authors.forename: Johannes
authors.initials: J
authors.lastname: von Lintig
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics / Q000378:metabolism*; D000217:Acyltransferases / Q000378:metabolism; D000818:Animals; D018376:Cardiovascular Abnormalities / Q000196:embryology / Q000378:metabolism; D019465:Craniofacial Abnormalities / Q000196:embryology / Q000378:metabolism; D004195:Disease Models, Animal; D005123:Eye / Q000196:embryology / Q000201:enzymology / Q000378:metabolism; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D006706:Homeostasis; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009025:Morpholines / Q000378:metabolism; D041681:NIH 3T3 Cells; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D054839:Retinol-Binding Proteins, Plasma / Q000235:genetics / Q000378:metabolism*; D013577:Syndrome; D013997:Time Factors; D014161:Transduction, Genetic; D014212:Tretinoin / Q000378:metabolism; D014801:Vitamin A / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D009025:Morpholines; D016376:Oligonucleotides, Antisense; C101326:RBP4 protein, human; C516065:Rbp4 protein, zebrafish; D054839:Retinol-Binding Proteins, Plasma; C519685:STRA6 protein, human; C000614448:STRA6 protein, zebrafish; D029961:Zebrafish Proteins; D014801:Vitamin A; D014212:Tretinoin; D000217:Acyltransferases; C056942:lecithin-retinol acyltransferase