Carotenoid Uptake and Protection in Cultured RPE - Carotenoids: Physical, Chemical, and Biological Functions and Properties - page 320

to be localized predominantly at the basal surface of the RPE (Anderson et al., 2001). In polarized,
cultured RPE cells, ApoE has been secreted both at the apical and basal sides, and its secretion has
been stimulated by the presence of HDL (Ishida et al., 2004).
ApoJ is another protein component of HDL which is highly expressed by the RPE and neural
retina, especially under oxidative stress conditions (Wong et al., 2000, 2001). It can act as a comple-
ment regulatory protein, which by binding to and inactivating the membrane-attack complex can
prevent cytolysis (Bartl et al., 2001). ApoJ accumulation was identii ed in drusen in AMD patients
(Sakaguchi et al., 2002; Wong et al., 2000).
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.
15.3.2.4 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 respon-
sible 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 efl ux from cells of lipophilic molecules can be mediated by sev-
eral members of the ATP-binding cassette (ABC) transporters family, some of which have been
identii ed in the brain, including the retina (Kim et al., 2008; Sarkadi et al., 2006).
One of those transporters is an ABC transporter A1 (ABCA1) which is widely expressed, with
particularly high expression in the adrenal gland and uterus and moderate expression in the liver and
brain (Kim et al., 2008). In human neuronal tissue ABCA1 is expressed by multiple cell types: iso-
lated human fetal neurons, microglia, astrocytes, and oligodendrocytes (Kim et al., 2008). ABCA1
has been identii ed in both the RPE and neural retina (Bailey et al., 2004; Lakkaraju et al., 2007;
Tserentsoodol et al., 2006a). The most extensively investigated function of ABCA1 is its role in
reverse transport of lipids from cells via HDLs to the liver (Faulkner et al., 2008; Lakkaraju et al.,
2007; Lorenzi et al., 2008). Importantly, ABCA1 also mediates intracellular efl ux of cholesterol
from late endosomes/lysosomes (Chen et al., 2001).
The importance of ABCA1 in carotenoid uptake into the retina is evident from studies on the
Wisconsin hypo-alpha mutant (WHAM) chicken having a recessive sex-linked mutation in the
ABCA1 transporter gene (Connor et al., 2007). Proper function of ABCA1 is essential for the for-
mation of HDLs (Faulkner et al., 2008; Tserentsoodol et al., 2006a). The mutant chicken exhib-
its a severe dei ciency of HDLs, having levels as much as 18.8 times smaller than in the control
chicken (Connor et al., 2007). Normally, HDLs are the predominant lipoproteins in chicken plasma,
accounting for 88% of total lipoproteins in the control chicken. In the WHAM chicken, HDLs
account for only 15% of total lipoproteins. The level of total lipoproteins in the mutant chicken is 3.2
times smaller than in the control chicken. The partial compensation for the lipoprotein concentra-
tion in the mutant chicken is due to a 1.5-fold increased level of LDLs in comparison to the control
chicken.
Importantly, the mutant chicken exhibits lower levels of lutein and zeaxanthin in plasma and
several other tissues in comparison with the control chicken, and that difference is already appar-
ent in 1-day-old chickens and remains in 28-day-old chickens fed the same diet (Connor et al.,
2007). In the WHAM chickens, the levels of lutein in the plasma, retina, skin, adipose tissue, liver
and heart, respectively, have been found to be only 8%, 10%, 18%, 33%, 52%, and 60% of the cor-
responding levels in control chickens. Even though the diet in these chickens included three times
more lutein than zeaxanthin and these ratios have been present in the plasma of both the control and
WHAM chickens, there was a preferential accumulation of zeaxanthin over lutein in their retinas.