Astaxanthin Enhances ATP-Binding Cassette Transporter A1/G1 Expressions and Cholesterol Efflux from Macrophages
Astaxanthin Enhances ATP-Binding Cassette Transporter A1/G1 Expressions and Cholesterol Efflux from Macrophages
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DOI：
10.3177/jnsv.58.96
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发表时间：
2012-04-01
影响因子：
1.6
通讯作者：
Ikewaki, Katsunori
中科院分区：
文献类型：
--
作者：
Iizuka, Maki;Ayaori, Makoto;Ikewaki, Katsunori
三磷酸腺苷结合盒转运体(ABC)A1和G1是巨噬细胞胆固醇外流的关键分子，是高密度脂蛋白(高密度脂蛋白)的主要抗动脉粥样硬化特性--胆固醇反向转运(RCT)的第一步。虾青素是一种天然存在的类胡萝卜素，导致各种生物体内的粉红色色素沉着。尽管虾青素被认为是一种强大的抗氧化剂，但它通过什么作用机制影响巨噬细胞中的胆固醇稳态仍不清楚。因此，我们研究了虾青素对巨噬细胞胆固醇外流和ABCA1/G1表达的影响。虾青素促进载脂蛋白A-I和高密度脂蛋白介导的胆固醇从RAW264.7细胞外流。在支持这些增强的胆固醇外流机制中，虾青素促进了ABCA1/G1在各种巨噬细胞中的表达。相比之下，虾青素对过氧化物酶体增殖物激活受体γ、肝X受体(LXR)α和LXRβ水平没有影响。用放线菌素D进行的实验表明，虾青素可在转录水平上诱导ABCA1/G1的表达，而胆固醇磺基转移酶过表达导致的氧固醇耗竭则进一步表明，这些诱导作用不依赖于LXR介导的信号转导途径。最后，我们使用人ABCA1/G1启动子-报告构建物进行荧光素酶活性检测，发现虾青素激活这两个启动子，而不考虑LXR反应元件的存在或不存在，表明这些激活不依赖LXR。总之，虾青素增加了ABCA1/G1的表达，从而以一种不依赖LXR的方式促进了apoA-I/HDL介导的胆固醇从巨噬细胞流出。因此，除了抗氧化特性外，虾青素潜在的心脏保护特性可能与高密度脂蛋白增强的抗动脉粥样硬化功能有关。
ATP-binding cassette transporters (ABC) A1 and G1 are key molecules in cholesterol efflux from macrophages, which is an initial step of reverse cholesterol transport (RCT), a major anti-atherogenic property of high-density lipoprotein (HDL). Astaxanthin is one of the naturally occurring carotenoids responsible for the pink-red pigmentation in a variety of living organisms. Although astaxanthin is known to be a strong antioxidant, it remains unclear through what mechanism of action it affects cholesterol homeostasis in macrophages. We therefore investigated the effects of astaxanthin on cholesterol efflux and ABCA1/G1 expressions in macrophages. Astaxanthin enhanced both apolipoprotein (apo) A-I- and HDL-mediated cholesterol efflux from RAW264.7 cells. In supporting these enhanced cholesterol efflux mechanisms, astaxanthin promoted ABCA1/G1 expression in various macrophages. In contrast, peroxisome proliferator-activated receptor gamma, liver X receptor (LXR) alpha and LxR beta levels remained unchanged by astaxanthin. An experiment using actinomycin D demonstrated that astaxanthin transcriptionally induced ABCA1/G1 expression, and oxysterol depletion caused by overexpression of cholesterol sulfotransferase further revealed that these inductions in ABCA1/G1 were independent of LXR-mediated pathways. Finally, we performed luciferase assays using human ABCA1/G1 promoter-reporter constructs to reveal that astaxanthin activated both promoters irrespective of the presence or absence of LXR-responsive elements, indicating LXR-independence of these activations. In conclusion, astaxanthin increased ABCA1/G1 expression, thereby enhancing apoA-I/HDL-mediated cholesterol efflux from the macrophages in an LXR-independent manner. In addition to the anti-oxidative properties, the potential cardioprotective properties of astaxanthin might therefore be associated with an enhanced anti-atherogenic function of HDL.