Receptor-Mediated Cellular Uptake Mechanism That Couples to Intracellular Storage

Abstract

Cells are known to take up molecules through membrane transport mechanisms such as active transport, channels, and facilitated transport. We report here a new membrane transport mechanism that employs neither cellular energy like active transport nor a preexisting electrochemical gradient of the free substrate like channels or facilitated transport. Through this mechanism, cells take up vitamin A bound with high affinity to retinol binding protein (RBP) in the blood. This mechanism is mediated by the RBP receptor STRA6, which defines a new type of cell-surface receptor. STRA6 is essential for the proper functioning of multiple human organs, but the mechanisms that enable and control its cellular vitamin A uptake activity are unknown. We found that STRA6-mediated vitamin A uptake is tightly coupled to specific intracellular retinoid storage proteins, but no single intracellular protein is absolutely required for its transport activity. By developing sensitive real-time monitoring techniques, we found that STRA6 is not only a membrane receptor but also catalyzes vitamin A release from RBP. However, vitamin A released from RBP by STRA6 inhibits further vitamin A release by STRA6 unless specific intracellular retinoid storage proteins relieve this inhibition. This mechanism is responsible for its coupling to intracellular storage proteins. The coupling of uptake to storage provides high specificity in cellular uptake of vitamin A and prevents the excessive accumulation of free vitamin A. We have also identified a robust small molecule-based technique to specifically stimulate cellular vitamin A uptake. This technique has implications in treating human diseases.

Lecithin:Retinol Acyltransferase Is Critical for Cellular Uptake of Vitamin A from Serum Retinol-binding Protein

“…for trapping of glucose by ATP-dependent phosphorylation). Besides LRAT, CRBP1 was suggested as an intracellular ROL acceptor from in vitro studies (16). Interestingly, we found that Lrat Ϫ/Ϫ mice displayed relatively high levels of CRBP1 in tissues as compared with control mice used in this study.…”

“…In cell culture studies, CRBP1 has been implicated in STRA6-mediated vitamin A uptake (16). Interestingly, Lrat Ϫ/Ϫ mice showed elevated CRBP1 protein in the liver, lung, and adipose tissue as compared with wild type control animals (Fig.…”

“…Function-Previous cell culture studies implicated LRAT in the uptake of vitamin A from holo-RBP (12,15,16). To analyze the role of LRAT for this process in vivo, we devised a method to measure cellular vitamin A uptake from holo-RBP in mice.…”

“…Cell culture studies indicate that the flux of ROL between RBP and STRA6 is bidirectional and that cellular accumulation of ROL depends on the cellular vitamin A-binding protein 1 (CRBP1) and lecithin:ROL acyltransferase (LRAT) (15,16). LRAT is a microsomal membrane-anchored enzyme that converts ROL into RE by transferring palmitate from the sn-2 position of lecithin (17).…”

Antioxidant Vitamins and Their Use in Psychiatry

“…[22] STRA6, sadece retinol bağlayıcı proteini bağlamakla kalmaz aynı zamanda vitamin A-RBP kompleksinden vitamin A' nın ayrılmasını katalize eder. [22,23] Embryonik gelişimde ve erişkinde yaygın olarak eksprese edilen bu molekülün aynı zamanda koroid pleksus da dahil olmak üzere çeşitli beyin bölgelerinde ekpresyonu mevcuttur. [24] …”