Astaxanthin enhances ATP-binding cassette transporter A1/G1 expressions and cholesterol efflux from macrophages.
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.
Institute of Environmental Science for Human Life, Ochanomizu University, 2-1-1, Otsuka, Tokyo, Japan.
Maki
M
Iizuka
Makoto
M
Ayaori
Harumi
H
Uto-Kondo
Emi
E
Yakushiji
Shunichi
S
Takiguchi
Kazuhiro
K
Nakaya
Tetsuya
T
Hisada
Makoto
M
Sasaki
Tomohiro
T
Komatsu
Makiko
M
Yogo
Yoshimi
Y
Kishimoto
Kazuo
K
Kondo
Katsunori
K
Ikewaki
D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000502:physiology; D000818:Animals; D000975:Antioxidants; D016632:Apolipoprotein A-I / Q000187:drug effects / Q000502:physiology; D002316:Cardiotonic Agents; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects*; D008074:Lipoproteins / Q000235:genetics* / Q000502:physiology; D008075:Lipoproteins, HDL / Q000187:drug effects / Q000502:physiology; D000071518:Liver X Receptors; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D057093:Orphan Nuclear Receptors / Q000502:physiology; D024341:Xanthophylls / Q000494:pharmacology
C577836:ABCA1 protein, human; C487540:ABCG1 protein, mouse; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D000975:Antioxidants; D016632:Apolipoprotein A-I; D002316:Cardiotonic Agents; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D024341:Xanthophylls; C005948:astaxanthine; D002784:Cholesterol