STRA6-Catalyzed Vitamin A Influx, Efflux, and Exchange

Abstract

Vitamin A has diverse biological functions and is essential for human survival. STRA6 is the high-affinity membrane receptor for plasma retinol binding protein (RBP), the principle and specific carrier of vitamin A (retinol) in the blood. It was previously shown that STRA6 couples to lecithin retinol acyltransferase (LRAT) and cellular retinol binding protein I (CRBP-I), but poorly to CRBP-II, for retinol uptake from holo-RBP. STRA6 catalyzes both retinol release from holo-RBP, which is responsible for its retinol uptake activity, and the loading of free retinol into apo-RBP, which can cause retinol efflux. Although STRA6-catalyzed retinol efflux into apo-RBP can theoretically deplete cells of retinoid, it is unclear to what extent this efflux happens and in what context. We show here that STRA6 can couple strongly to both CRBP-I and CRBP-II for retinol efflux to apo-RBP. Strikingly, pure apo-RBP can cause almost complete depletion of retinol taken up by CRBP-I in a STRA6-dependent manner. However, if STRA6 encounters both holo-RBP and apo-RBP (as in blood), holo-RBP blocks STRA6-mediated retinol efflux by competing with apo-RBP's binding to STRA6 and by counteracting retinol efflux with influx. We also found that STRA6 catalyzes efficient retinol exchange between intracellular CRBP-I and extracellular RBP, even in the presence of holo-RBP. STRA6's retinol exchange activity may serve to refresh the intracellular retinoid pool. This exchange is also a previously unknown function of CRBP-I and distinguishes CRBP-I from LRAT.

Retinol and retinyl esters: biochemistry and physiology

“…This receptor interacts with RBP4 and increases cellular uptake of retinol ( 95 ). In addition, STRA6 is reported to facilitate retinol effl ux from cells (98)(99)(100). Both LRAT and CRBPI are retinol or retinoic acid, is not different from the delivery of vitamin D or thyroid hormone, involving the presence of relatively large concentrations of the transcriptionally inactive precursor (retinol, 25-hydroxy-vitamin D, or T 4 ) and relatively low concentrations of the transcriptionally active metabolite (retinoic acid, 1,25-dihydroxy-vitamin D, or T 3 ).…”

“…proposed to couple with STRA6 within the cell ( 95,100,101 ). von Lintig and colleagues have convincingly established that the functional coupling of LRAT with STRA6 increases cellular retinol uptake into tissues and have proposed that LRAT is a critical component of this process ( 101 ).…”

“…von Lintig and colleagues have convincingly established that the functional coupling of LRAT with STRA6 increases cellular retinol uptake into tissues and have proposed that LRAT is a critical component of this process ( 101 ). In vitro experiments have established that STRA6 facilitates effi cient retinol exchange between intercellular CRBPI and extracellular RBP4 ( 100 ). Recently, mice lacking STRA6 were generated and studied ( 102 ).…”

Retinol oxidation to retinoic acid in human thyroid glandular cells

“…The scheme describes retinoid metabolism in the different cellular compartments. In the cell plasma membrane retinol exchange between apo-CRBP1 and holo-RBP is mediated by STRA6 receptor (Stimulated by Retinoic Acid 6) 50 . In the endoplasmic reticulum, the relative ratio of holo-CRBP1 to apo-CRBP1 is influenced by retinyl ester hydrolase (REH) or by lecithin retinol acyltransferase (LRAT).…”

How Free Retinol Behaves Differently from RBP-Bound Retinol in RBP Receptor-Mediated Vitamin A Uptake

“…Contrary to the claim by Berry et al, STRA6 has no problem in taking up vitamin A from the natural holo-RBP/TTR complex (4,5,8), and TTR partially, but not completely, inhibits STRA6's interaction with holo-RBP (5). Berry et al did not perform any high-performance liquid chromatography (HPLC) analysis or any assay of vitamin A uptake from serum, the natural source of the RBP/TTR complex.…”