Despite its serious adverse effects, recent accumulating evidence suggests that a physiological
retinoic acid receptor (RAR) agonist,
all-trans retinoic acid (atRA), exhibits preventive effects on
atherogenesis. Therefore, the present study was designed to explore novel natural RAR
ligands with anti-atherogenic effects in order to identify and develop a
drug without severe side effects. Among
xanthophylls and
carotenoids studied,
beta-cryptoxanthin and
lutein exhibited RAR
ligand activity in yeast two-hybrid system that was found to be completely abolished by the RAR pan-antagonist
LE540. Furthermore, these molecules can bind the RAR
ligand-binding domain in the
CoA-BAP system but not RXR
ligand-binding domain. These results indicate that both
beta-cryptoxanthin and
lutein serve as
ligands for RAR, but not RXR, although their binding affinity was three orders of magnitude lower than that of atRA. Additionally, when applied to macrophages,
beta-cryptoxanthin indeed was found to induce the
ATP-binding cassette transporter A1 (ABCA1) and ABCG1 mRNAs, which exert anti-atherosclerotic effects by preventing
cholesteryl ester accumulation in macrophages. The induction of ABCA1
proteins by
beta-cryptoxanthin as well as atRA was abrogated by
LE540. In summary,
beta-cryptoxanthin appears to be more an efficient
provitamin A source than other
carotenoids and
xanthophylls including
beta-carotene, since
beta-cryptoxanthin can act not only as a RAR agonist but also a source of
vitamin A. Taking into account that the pharmacodynamics difference between
beta-cryptoxanthin and atRA,
beta-cryptoxanthin appears to exert beneficial effects on
atherogenesis through RAR activation in the manner different from atRA.