title: The retinol esterifying enzyme LRAT supports cell signaling by retinol-binding protein and its receptor STRA6.
abstract: Vitamin A, retinol, circulates in blood bound to retinol-binding protein (RBP). At some tissues, holo-RBP is recognized by a plasma membrane receptor termed STRA6, which serves a dual role: it mediates transport of retinol from RBP into cells, and it functions as a cytokine receptor that, on binding holo-RBP, activates JAK2/STAT5 signaling. As STAT target genes include SOCS3, an inhibitor of insulin receptor, holo-RBP suppresses insulin responses in STRA6-expressing cells. We have shown previously that the two functions of STRA6 are interdependent. These observations suggest factors that regulate STRA6-mediated retinol transport may also control STRA6-mediated cell signaling. One such factor is retinol metabolism, which enables cellular uptake of retinol by maintaining an inward-directed concentration gradient. We show here that lecithin:retinol acyl transferase (LRAT), which catalyzes esterification of retinol to its storage species retinyl esters, is necessary for activation of the STRA6/JAK2/STAT5 cascade by holo-RBP. In accordance, LRAT-null mice are protected from holo-RBP-induced suppression of insulin responses. Hence, STRA6 signaling, which requires STRA6-mediated retinol transport, is supported by LRAT-catalyzed retinol metabolism. The observations demonstrate that STRA6 regulates key cellular processes by coupling circulating holo-RBP levels and intracellular retinol metabolism to cell signaling.
authors.affiliation: 2Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA. noa.noy@case.edu.
authors.forename: Gurdeep
authors.initials: G
authors.lastname: Marwarha
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Berry
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Croniger
authors.forename: Noa
authors.initials: N
authors.lastname: Noy
mesh_terms: D000217:Acyltransferases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004435:Eating / Q000502:physiology; D005951:Glucose Tolerance Test; D056945:Hep G2 Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D060888:Real-Time Polymerase Chain Reaction; D012177:Retinol-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism; D014801:Vitamin A / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D012177:Retinol-Binding Proteins; C519685:STRA6 protein, human; C547866:STRA6 protein, rat; C491411:Socs3 protein, mouse; C108001:Stra6 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014801:Vitamin A; D000217:Acyltransferases; C056942:lecithin-retinol acyltransferase
keywords: JAK; STAT; cytokine receptors; insulin receptor; obesity; vitamin A metabolism
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