β-Cryptoxanthin, a novel natural RAR ligand, induces ATP-binding cassette transporters in macrophages

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, β-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 β-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, β-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 β-cryptoxanthin as well as atRA was abrogated by LE540. In summary, β-cryptoxanthin appears to be more an efficient provitamin A source than other carotenoids and xanthophylls including β-carotene, since β-cryptoxanthin can act not only as a RAR agonist but also a source of vitamin A. Taking into account that the pharmacodynamics difference between β-cryptoxanthin and atRA, β-cryptoxanthin appears to exert beneficial effects on atherogenesis through RAR activation in the manner different from atRA.