Retina transporters

T. Nakashima, M. Tomi, K. Katayama, M. Tachikawa, M. Watanabe, T. Terasaki, and K. Hosoya. Blood-to-retina transport of creatine via creatine transporter (CRT) at the rat inner blood-retinal barrier. J. Neumchem. 89 1454—1461... 

Carotenoids are also present in animals, including humans, where they are selectively absorbed from diet (Furr and Clark 1997). Because of their hydrophobic nature, carotenoids are located either in the lipid bilayer portion of membranes or form complexes with specific proteins, usually associated with membranes. In animals and humans, dietary carotenoids are transported in blood plasma as complexes with lipoproteins (Krinsky et al. 1958, Tso 1981) and accumulate in various organs and tissues (Parker 1989, Kaplan et al. 1990, Tanumihardjo et al. 1990, Schmitz et al. 1991, Khachik et al. 1998, Hata et al. 2000). The highest concentration of carotenoids can be found in the eye retina of primates. In the retina of the human eye, where two dipolar carotenoids, lutein and zeaxan-thin, selectively accumulate from blood plasma, this concentration can reach as high as 0.1-1.0mM (Snodderly et al. 1984, Landrum et al. 1999). It has been shown that in the retina, carotenoids are associated with lipid bilayer membranes (Sommerburg et al. 1999, Rapp et al. 2000) although, some macular carotenoids may be connected to specific membrane-bound proteins (Bernstein et al. 1997, Bhosale et al. 2004). 

RPE plays numerous functions essential for proper structure and function of retinal photoreceptors. They include the maintenance of the blood-retina barrier, selective uptake and transport of nutrients from the blood to the retina and removal of waste products to the blood, enzymatic cleavage of P-carotene into vitamin A, storage of vitamin A and its metabolic transformations, phagocytosis and molecular renewal of POS, expression and secretion of growth factors and immunomodulatory cytokines (Aizman et al., 2007 Aleman et al., 2001 Crane et al., 2000a,b Elner et al., 2006 Holtkamp et al., 2001 Leuenberger et al., 2001 Lindqvist and Andersson, 2002 Maminishkis et al., 2006 Momma et al., 2003 Strauss, 2005). 

Interestingly, carotenoids more abundant in the blood plasma than zeaxanthin, such as lycopene, P-carotene, and P-cryptoxanthin, do not accumulate in the retina. RPE cells express p,p-carotene 15,15 -monooxygenase (BCO), formerly known as P-carotene 15,l5 -dioxygcnase, an enzyme that catalyzes the oxidative cleavage of P-carotene into two molecules of all-trans-retinal (Aleman et al., 2001 Bhatti et al., 2003 Chichili et al., 2005 Leuenberger et al., 2001 Lindqvist and Andersson, 2002). Therefore it may be suggested that p -carotene transported into RPE-cells is efficiently cleaved into retinal molecules. BCO cleaves also P-cryptoxanthin (Lindqvist and Andersson, 2002), and its absence in the retina may also be explained by its efficient cleavage to retinoids. However, lycopene, often the most abundant carotenoid in human plasma, cannot serve as a substrate for BCO, and yet it is not detectable in the neural retina (Khachik et al., 2002). 

The greatest concentration of the macular pigment is present in the avascular part of the retina. This suggests that the RPE may play the predominant role in uptake and transport of xanthophylls to the photoreceptors. Moreover, about 25% of the total retinal xanthophylls are present in the POS (Rapp et al., 2000 Sommerburg et al., 1999), which, under normal conditions, are intimately associated with the RPE. This proximity lends further support to the hypothesis of a role for the RPE in the selective uptake of carotenoids into the retina. 

Recent data indicate that SR-BI is a nonspecific receptor for many lipophilic molecules (Lorenzi et al., 2008 Reboul et al., 2007b). Apart from HDLs, rodent SR-BI also binds to LDL, VLDL, acetylated LDL, oxidized LDL, and maleylated bovine serum albumin. SR-BII has a similar ligand specificity and function to that of SR-BI (Webb et al., 1998). However, it has been shown that vitamin E (which like carotenoids is carried in the bloodstream mainly by LDL and HDL) is transported more efficiently into the endothelial cells from HDLs than from LDLs (Balazs et al., 2004 Kaempf-Rotzoll et al., 2003 Mardones and Rigotti, 2004). This is in striking contrast to cholesterol, which is taken up much more efficiently from LDLs than HDLs by the RPE to the retina (Tserentsoodol et al., 2006b). It remains to be shown which lipoproteins are the main carriers for carotenoids transported from blood into the RPE. 

The expression of all these apo-lipoproteins by the RPE, and its ability to form lipoprotein particles suggest that these newly formed lipoproteins may be involved in the transport of lipophilic molecules, including carotenoids, from the RPE to the neural retina and/or to the choroidal blood supply. Testing the roles of apolipoproteins and lipoprotein particles in carotenoid secretion from the RPE is another subject awaiting experimental investigation. 

Transporters Potentially Involved in Carotenoid Movement in the Retina... 

While it may be speculated that in the RPE both lipoprotein and/or scavenger receptors are likely to be involved in carotenoid uptake from the blood, it is not clear what mechanism(s) are responsible for carotenoid transport through the RPE into the neural retina. Also, it is not clear what mechanism(s) are responsible for selective accumulation in the retina of only two carotenoids. 

Intracellular transport and efflux from cells of lipophilic molecules can be mediated by several members of the ATP-binding cassette (ABC) transporters family, some of which have been identified in the brain, including the retina (Kim et al., 2008 Sarkadi et al., 2006). 

In addition to its presence in the RPE, ABCA1 has been found to be localized in the neural retina, particularly in the ganglion cell layer and rod photoreceptor inner segments (Tserentsoodol et al., 2006a), suggesting it may be involved in carotenoid transport throughout the retina. 

Apart from SR-BI, SR-BII, CD36, and ABCA1, a microarray analysis of gene expression in human RPE reveals some additional lipid transporters that might potentially be involved in intracellular transport of carotenoids and/or their efflux from the RPE cells into the neural retina or out of the retina into the choroidal blood (van Soest et al., 2007). These include other ABC... 

Altogether, the role of transporters of lipophilic molecules regulating the movement of carotenoids through the RPE and into the neural retina is another area awaiting experimental investigation. 

SR-BI is highly abundant in POS (Tserentsoodol et al., 2006a). Therefore it may be speculated that it plays a role in further uptake of carotenoid-enriched (lipo)proteins and their transport from the outer segment and then into deeper layers of the retina. 

Altogether, there are many unknowns about carotenoid transport in the retina. However, present knowledge on carotenoid uptake in other cell types and the finding of multiple proteins potentially involved in carotenoid transport in the RPE and adjacent neural retina leads to the suggestion that several hypothetical pathways exist (Figure 15.3). Many such pathways can be easily tested in cultured RPE. 

Connor, WE, Duell, PB, Kean, R, and Wang, Y, 2007. The prime role of HDL to transport lutein into the retina Evidence from HDL-deficient WHAM chicks having a mutant ABCA1 transporter. Invest Ophthalmol Vis Sci 48, 4226—4231. 

Wang, N and Anderson, RE, 1993. Transport of 22 6n-3 in the plasma and uptake into retinal pigment epithelium and retina. Exp Eye Res 57, 225-233. 

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