Transport of vitamin A across blood‐tissue barriers is facilitated by STRA6

Abstract

Vitamin A bound to retinol binding protein 4 (RBP4) constitutes the major transport mode for retinoids in fasting circulation. Emerging evidence suggests that membrane protein, STRA6 (stimulated by retinoic acid 6), is the RBP4 receptor and vitamin A channel; however, the role of STRA6 in vitamin A homeostasis remains to be defined in vivo. We subjected Stra6-knockout mice to diets sufficient and insufficient for vitamin A and used heterozygous siblings as controls. We determined vitamin A levels of the eyes, brain, and testis, which highly express Stra6, as well as of tissues with low expression, such as lung and fat. We also studied the consequence of STRA6 deficiency on retinoid-dependent processes in tissues. Furthermore, we examined how STRA6 deficiency affected retinoid homeostasis of the aging mouse. The picture that emerged indicates a critical role for STRA6 in the transport of vitamin A across blood-tissue barriers in the eyes, brain, and testis. Concurrently, fat and lung rely on dietary vitamin A. In testis and brain, Stra6 expression was regulated by vitamin A. In controls, this regulation reduced vitamin A consumption when the dietary supply was limited, sequestering it for the eye. Thus, STRA6 is critical for vitamin A homeostasis and the adaption of this process to the fluctuating supply of the vitamin.

The role of the retinoids in schizophrenia: genomic and clinical perspectives

“…Regarding transport to the brain, the role of these secondary pathways is still not well characterised. STRA6 is highly expressed by the blood-brain barrier (BBB), which suggests the RBP4-TTR mechanism facilitates entry into neural tissues-supported by in vivo evidence from Stra6 −/− mice where neural retinol homoeostasis is disturbed [24,26,27]. As retinol delivery to the brain is essential for subsequent at-RA biosynthesis, specific factors which may regulate transport and passage across the BBB should be investigated further, particularly as localised neural retinoid deficiency would be of particular phenotypic relevance to schizophrenia.…”

“…TTR, once complexed with RBP4 bound retinol, plays an important role in determining serum retinol concentration via downregulating renal filtration of the RBP4 protein [23]. While the mechanisms underpinning cellular retinol influx from the TTR/retinol/RBP4 pathway are not fully resolved, the membrane protein STRA6 (stimulated by retinoic acid 6) has been implicated in bi-directional retinol transport across the cell membrane [24,25], with decreased retinol concentrations observed in homozygous Stra6 −/− knock-out mice in several tissues including the brain and retina [26,27] (Fig. 1b).…”

Vitamin A supplementation redirects the flow of retinyl esters from peripheral to central organs of neonatal rats raised under vitamin A–marginal conditions

“…During the second half of the suckling period (wP 10-wP 21), LPL activity declines in the liver and increases in other tissues, such as the heart, skeletal muscle, and kidney, reaching adult levels at weaning (39)(40)(41). Meanwhile, the expression of STRA6 decreases in the lungs (27) and other extrahepatic tissues (27,42). This timing overlaps with a 2 The stomach model did not include a CM-RE uptake component.…”

Recent insights on the role and regulation of retinoic acid signaling during epicardial development

“…Beside retinol import in cells, there is evidence that STRA6 is also involved in efflux of retinol from cells to the extracellular compartment to release retinol in association with RBP4 for redistribution (Kawaguchi, Zhong, Kassai, Ter-Stepanian, & Sun, 2012;Kelly & von Lintig, 2015). STRA6 has also been found to be responsible for transferring retinol across the blood-tissue barriers in adults and it is likely involved in the transfer of RBP4-delivered retinol across the placenta (Bouillet et al, 1997;Kelly, Widjaja-Adhi, Palczewski, & von Lintig, 2016;Sapin et al, 2000). STRA6 has also been found to be responsible for transferring retinol across the blood-tissue barriers in adults and it is likely involved in the transfer of RBP4-delivered retinol across the placenta (Bouillet et al, 1997;Kelly, Widjaja-Adhi, Palczewski, & von Lintig, 2016;Sapin et al, 2000).…”

“…As its name implies, Stra6 is induced by RA, therefore, this dynamic equilibrium could be important in cases of excess accumulation of retinoids in tissues. STRA6 has also been found to be responsible for transferring retinol across the blood-tissue barriers in adults and it is likely involved in the transfer of RBP4-delivered retinol across the placenta (Bouillet et al, 1997;Kelly, Widjaja-Adhi, Palczewski, & von Lintig, 2016;Sapin et al, 2000). In addition to RBP4, serum amyloid A can bind retinol with high affinity and was suggested to act as an alternate serum transporter for retinol in situations in which the expression of RBP4 is reduced such as during an acute phase response (Derebe et al, 2014;Rosales, Ritter, Zolfaghari, Smith, & Ross, 1996).…”