This study was conducted to explore the effect of zerumbone, isolated from Zingiber zerumbet Smith, on apolipoprotein A-I (apoA-I)-mediated cholesterol efflux from THP-1 macrophages. THP-1 macrophages were treated with different concentrations (10-100 μmol/l) of zerumbone and cholesterol efflux was measured. The involvement of ATP-binding cassette (ABC) transporters ABCA1 and ABCG1 and ERK1/2 signaling was checked. Notably, zerumbone caused a concentration-dependent induction of ABCA1 but not ABCG1, coupled with enhanced phosphorylation of ERK1/2. Pre-treatment with PD98059 (a potent ERK1/2 inhibitor) significantly blocked the upregulation of ABCA1 by zerumbone. Small interfering RNA-mediated downregulation of ABCA1 but not ABCG1 significantly impaired the promotion of apoA-I-mediated cholesterol efflux by zerumbone. Taken together, zerumbone has the capacity to facilitate apoA-I-mediated cholesterol efflux from macrophages through the activation of ERK1/2 signaling and upregulation of ABCA1.

Keywords:
ATP-binding cassette transporter, Cholesterol efflux, Zerumbone, Macrophages, Signaling pathway
1.
Moore KJ, Sheedy FJ, Fisher EA: Macrophages in atherosclerosis: a dynamic balance. Nat Rev Immunol 2013;13:709-721.
2.
Yu XH, Fu YC, Zhang DW, Yin K, Tang CK: Foam cells in atherosclerosis. Clin Chim Acta 2013;424:245-252.
3.
Cuchel M, Rader DJ: Macrophage reverse cholesterol transport: key to the regression of atherosclerosis? Circulation 2006;113:2548-2555.
4.
Cavelier C, Lorenzi I, Rohrer L, von Eckardstein A: Lipid efflux by the ATP-binding cassette transporters ABCA1 and ABCG1. Biochim Biophys Acta 2006;1761:655-666.
5.
Murakami A, Takahashi D, Kinoshita T, Koshimizu K, Kim HW, Yoshihiro A, Nakamura Y, Jiwajinda S, Terao J, Ohigashi H: Zerumbone, a Southeast Asian ginger sesquiterpene, markedly suppresses free radical generation, proinflammatory protein production, and cancer cell proliferation accompanied by apoptosis: the alpha,beta-unsaturated carbonyl group is a prerequisite. Carcinogenesis 2002;23:795-802.
6.
Yodkeeree S, Sung B, Limtrakul P, Aggarwal BB: Zerumbone enhances TRAIL-induced apoptosis through the induction of death receptors in human colon cancer cells: evidence for an essential role of reactive oxygen species. Cancer Res 2009;69:6581-6589.
7.
Tzeng TF, Liou SS, Chang CJ, Liu IM: Zerumbone, a tropical ginger sesquiterpene, ameliorates streptozotocin-induced diabetic nephropathy in rats by reducing the hyperglycemia-induced inflammatory response. Nutr Metab (Lond) 2013;10:64.
8.
Murakami A, Shigemori T, Ohigashi H: Zingiberaceous and citrus constituents, 1'-acetoxychavicol acetate, zerumbone, auraptene, and nobiletin, suppress lipopolysaccharide-induced cyclooxygenase-2 expression in RAW264.7 murine macrophages through different modes of action. J Nutr 2005;135(12 suppl):2987S-2992S.
9.
Eguchi A, Kaneko Y, Murakami A, Ohigashi H: Zerumbone suppresses phorbol ester-induced expression of multiple scavenger receptor genes in THP-1 human monocytic cells. Biosci Biotechnol Biochem 2007;71:935-945.
10.
Livak KJ, Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 2001;25:402-408.
11.
Kawashima RL, Medh JD: Down-regulation of lipoprotein lipase increases ABCA1-mediated cholesterol efflux in THP-1 macrophages. Biochem Biophys Res Commun 2014;450:1416-1421.
12.
Javaheri A, Rader DJ: Apolipoprotein A-I and cholesterol efflux: the good, the bad, and the modified. Circ Res 2014;114:1681-1683.
13.
Xu X, Li Q, Pang L, Huang G, Huang J, Shi M, Sun X, Wang Y: Arctigenin promotes cholesterol efflux from THP-1 macrophages through PPAR-γ/LXR-α signaling pathway. Biochem Biophys Res Commun 2013;441:321-326.
14.
Malekpour-Dehkordi Z, Javadi E, Doosti M, Paknejad M, Nourbakhsh M, Yassa N, Gerayesh-Nejad S, Heshmat R: S-Allylcysteine, a garlic compound, increases ABCA1 expression in human THP-1 macrophages. Phytother Res 2013;27:357-361.
15.
Bodzioch M, Orsó E, Klucken J, Langmann T, Böttcher A, Diederich W, Drobnik W, Barlage S, Büchler C, Porsch-Ozcürümez M, Kaminski WE, Hahmann HW, Oette K, Rothe G, Aslanidis C, Lackner KJ, Schmitz G: The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease. Nat Genet 1999;22:347-351.
16.
Christiansen-Weber TA, Voland JR, Wu Y, Ngo K, Roland BL, Nguyen S, Peterson PA, Fung-Leung WP: Functional loss of ABCA1 in mice causes severe placental malformation, aberrant lipid distribution, and kidney glomerulonephritis as well as high-density lipoprotein cholesterol deficiency. Am J Pathol 2000;157:1017-1029.
17.
Francone OL, Royer L, Boucher G, Haghpassand M, Freeman A, Brees D, Aiello RJ: Increased cholesterol deposition, expression of scavenger receptors, and response to chemotactic factors in Abca1-deficient macrophages. Arterioscler Thromb Vasc Biol 2005;25:1198-1205.
18.
Chen BY, Lin DP, Wu CY, Teng MC, Sun CY, Tsai YT, Su KC, Wang SR, Chang HH: Dietary zerumbone prevents mouse cornea from UVB-induced photokeratitis through inhibition of NF-κB, iNOS, and TNF-α expression and reduction of MDA accumulation. Mol Vis 2011;17:854-863.
19.
Shamoto T, Matsuo Y, Shibata T, Tsuboi K, Nagasaki T, Takahashi H, Funahashi H, Okada Y, Takeyama H: Zerumbone inhibits angiogenesis by blocking NF-κB activity in pancreatic cancer. Pancreas 2014;43:396-404.
20.
Lin XL, He XL, Zeng JF, Zhang H, Zhao Y, Tan JK, Wang Z: FGF21 increases cholesterol efflux by upregulating ABCA1 through the ERK1/2-PPARγ-LXRα pathway in THP1 macrophage-derived foam cells. DNA Cell Biol 2014;33:514-521.
21.
Zhou X, Yin Z, Guo X, Hajjar DP, Han J: Inhibition of ERK1/2 and activation of liver X receptor synergistically induce macrophage ABCA1 expression and cholesterol efflux. J Biol Chem 2010;285:6316-6326.
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2015
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