Astaxanthin Enhances ATP-Binding Cassette Transporter A1/G1 Expressions and Cholesterol Efflux from Macrophages
Institute of Environmental Science for Human Life, Ochanomizu University, 2-1-1, Otsuka, Tokyo, Japan.Journal of Nutritional Science and Vitaminology (Impact Factor: 0.83). 07/2012; 58(2):96-104. DOI: 10.3177/jnsv.58.96
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 γ, liver X receptor (LXR) α and LXRβ 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.
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ABSTRACT: Homocysteine (Hcy) has been recognized as a prevalent risk factor for cardiovascular events. Cholesterol-loaded foam cells are a central component of atherosclerotic lesions. ATP-binding cassette transporter A1 (ABCA1), which mediates the efflux of cellular cholesterol and phospholipids, is the rate-limiting step in lipid metabolism. Acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT1) promotes accumulation of cholesterol ester in macrophages, thereby resulting in the foam cell formation, a hallmark of early stage in atherosclerosis. In this study, cultured monocyte-derived foam cells were incubated with clinical relevant concentrations of Hcy for 24 h. Both increased number of foam cells and accumulation of cholesterol were found, and the mRNA and protein expression levels of ABCA1 were decreased, while ACAT1 expression was increased in the presence of Hcy. Furthermore, the DNA methylation level of ABCA1 gene was increased whereas ACAT1 DNA methylation was decreased by using different concentrations of Hcy. Moreover, our results showed that DNA methyltransferase (DNMT) activity and DNA methyltransferase 1 (DNMT1) mRNA expression were increased by Hcy. It is indicated that DNA methylation has the function to regulate the expression of ABCA1 and ACAT1 via DNMT. In conclusion, these results suggest that ABCA1 and ACAT1 DNA methylation induced by Hcy may play a potential role in ABCA1 and ACAT1 expression and the accumulation of cholesterol in monocyte-derived foam cells.Acta Biochimica et Biophysica Sinica 01/2013; 45(3). DOI:10.1093/abbs/gms119 · 2.19 Impact Factor
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ABSTRACT: The ATP-binding cassette A1 (ABCA1) transporter plays a major role in the efflux of lipids by mediating the cellular transport of phospholipids and cholesterol to lipid-poor/lipid-free apolipoprotein A-I (apoA-I) particles and thereby exerting important anti-atherogenic effects. Although the mechanism whereby ABCA1 mediates cholesterol efflux is not completely understood, numerous studies have shown that, in addition to apoA-I, the expression level of the total or cell surface ABCA1 protein is a determining factor for the activity of ABCA1-mediated cholesterol efflux, and defects in ABCA1-mediated cholesterol efflux lead to various pathological conditions in different cells, including cardiovascular and metabolic disorders. It has been widely demonstrated that a growing list of natural and synthetic substances and metabolic regulators that modulate the expression of ABCA1 not only act directly on the ABCA1 gene promoter, but also occurs at the post-transcriptional level via micro-RNAs and post-translationally through the stabilization or localization of the protein. The complex regulatory network of ABCA1 results in promoting or suppressing cholesterol efflux from cells, therefore we speculate that the ABCA1 transporter is emerging as a novel therapeutic target for cardiovascular and metabolic disorders. Thus, ABCA1 is a key modulator of cellular cholesterol efflux and contributes to functional disorders in different types of cells.Current pharmaceutical biotechnology 09/2013; 14(6). DOI:10.2174/138920101131400228 · 2.51 Impact Factor
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ABSTRACT: There is currently much interest in biological active compounds derived from natural resources, especially compounds that can efficiently act on molecular targets, which are involved in various diseases. Astaxanthin (3,3'-dihydroxy-β, β'-carotene-4,4'-dione) is a xanthophyll carotenoid, contained in Haematococcus pluvialis, Chlorella zofingiensis, Chlorococcum, and Phaffia rhodozyma. It accumulates up to 3.8% on the dry weight basis in H. pluvialis. Our recent published data on astaxanthin extraction, analysis, stability studies, and its biological activities results were added to this review paper. Based on our results and current literature, astaxanthin showed potential biological activity in in vitro and in vivo models. These studies emphasize the influence of astaxanthin and its beneficial effects on the metabolism in animals and humans. Bioavailability of astaxanthin in animals was enhanced after feeding Haematococcus biomass as a source of astaxanthin. Astaxanthin, used as a nutritional supplement, antioxidant and anticancer agent, prevents diabetes, cardiovascular diseases, and neurodegenerative disorders, and also stimulates immunization. Astaxanthin products are used for commercial applications in the dosage forms as tablets, capsules, syrups, oils, soft gels, creams, biomass and granulated powders. Astaxanthin patent applications are available in food, feed and nutraceutical applications. The current review provides up-to-date information on astaxanthin sources, extraction, analysis, stability, biological activities, health benefits and special attention paid to its commercial applications.Marine Drugs 01/2014; 12(1):128-152. DOI:10.3390/md12010128 · 2.85 Impact Factor
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