β-Cryptoxanthin, a novel natural RAR ligand, induces ATP-binding cassette transporters in macrophages
β-Cryptoxanthin, a novel natural RAR ligand, induces ATP-binding cassette transporters in macrophages
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DOI：
10.1016/j.bcp.2007.04.014
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发表时间：
2007-07-15
影响因子：
5.8
通讯作者：
Inoue, Makoto
中科院分区：
文献类型：
--
作者：
Matsumoto, Akira;Mizukami, Hajime;Inoue, Makoto
尽管有严重的副作用，但最近越来越多的证据表明，生理性视黄酸受体 (RAR) 激动剂全反式视黄酸 (atRA) 对动脉粥样硬化具有预防作用。因此，本研究旨在探索具有抗动脉粥样硬化作用的新型天然RAR配体，以鉴定和开发没有严重副作用的药物。在所研究的叶黄素和类胡萝卜素中，β-隐黄素和叶黄素在酵母双杂交系统中表现出RAR配体活性，但发现该活性被RAR全拮抗剂LE540完全消除。此外，这些分子可以结合 CoA-BAP 系统中的 RAR 配体结合结构域，但不能结合 RXR 配体结合结构域。这些结果表明，β-隐黄素和叶黄素均可作为 RAR 的配体，但不是 RXR，尽管它们的结合亲和力比 atRA 低三个数量级。此外，当应用于巨噬细胞时，β-隐黄素确实被发现可以诱导 ATP 结合盒转运蛋白 A1 (ABCA1) 和 ABCG1 mRNA，从而通过防止巨噬细胞中胆固醇酯积累来发挥抗动脉粥样硬化作用。 LE540 消除了 P-隐黄质和 atRA 对 ABCA1 蛋白的诱导作用。总之，β-隐黄素似乎是比其他类胡萝卜素和叶黄素（包括 β-胡萝卜素）更有效的维生素原 A 来源，因为 β-隐黄素不仅可以作为 RAR 激动剂，而且可以作为维生素 A 的来源。考虑到 β-隐黄素和 atRA 之间的药效学差异，β-隐黄素似乎通过与 atRA 不同的方式通过 RAR 激活对动脉粥样硬化产生有益作用。 (C) 2007 Elsevier Inc. 保留所有权利。
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 P-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. (C) 2007 Elsevier Inc. All rights reserved.