Akio Iio*†, Kenji Ohguchi†‡, Munekazu Iinuma§, Yoshinori Nozawa†, and Masafumi Ito†
† Gifu International Institute of Biotechnology, 1-1 Naka-Fudogaoka, Kakamigahara, Gifu 504-0838, Japan
‡ Department of Human Nutrition, Sugiyama Jogakuen University, 17-3 Hoshigaoka-Motomachi, Nagoya, Aichi 464-8662, Japan
§ Laboratory of Pharmacognosy, Gifu Pharmaceutical University, 1-25-4 Daigaku-Nishi, Gifu, Gifu 501-1196, Japan
Department of Food and Health, Tokai Gakuin University, 5-68 Naka-Kirinocho, Kakamigahara, Gifu 504-8511, Japan
J. Nat. Prod., Article ASAP
DOI: 10.1021/np200696r
Publication Date (Web): March 19, 2012
ABCA1, a member of the ATP-binding cassette transporter family, regulates high-density lipoprotein (HDL) metabolism and cholesterol transport. Its expression is upregulated mainly by the activation of the liver X receptor (LXR). Since ABCA1 plays a pivotal role in cholesterol and HDL metabolism, identification of a compound capable of increasing its expression may be beneficial for the prevention and therapy of atherosclerosis. Firefly luciferase reporter assays were developed for human ABCA1 promoters and LXR enhancers, and an in-house phytochemical library was screened. It was found that a citrus flavonoid, hesperetin (1), increased ABCA1 promoter and LXR enhancer activities in THP-1 macrophages. It was also found that this flavonoid promoted PPAR-enhancing activity. In accordance with these findings, 1 increased mRNA and protein expression of ABCA1 and consequently upregulated ApoA-I-mediated cholesterol efflux. These results provide evidence that 1 promotes ApoA-I-mediated cholesterol efflux from macrophages by increasing ABCA1 expression through the activation of LXRα and PPARγ.
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