Gifu International Institute of Biotechnology, 1-1 Naka-Fudogaoka, Kakamigahara, Gifu 504-0838, Japan.
J Nat Prod. 2012 Apr 27;75(4):563-6. doi: 10.1021/np200696r. Epub 2012 Mar 19.
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.
ABCA1 是 ATP 结合盒转运蛋白家族的一员，调节高密度脂蛋白（HDL）代谢和胆固醇转运。其表达主要通过肝 X 受体（LXR）的激活而上调。由于 ABCA1 在胆固醇和 HDL 代谢中起着关键作用，因此鉴定能够增加其表达的化合物可能有益于动脉粥样硬化的预防和治疗。已经为人类 ABCA1 启动子和 LXR 增强子开发了萤火虫荧光素酶报告基因测定法，并筛选了内部植物化学文库。发现一种柑橘类黄酮，桔皮素（1）可增加 THP-1 巨噬细胞中 ABCA1 启动子和 LXR 增强子的活性。还发现这种类黄酮促进了 PPAR 增强活性。根据这些发现，1 增加了 ABCA1 的 mRNA 和蛋白表达，从而通过激活 LXRα 和 PPARγ 增加载脂蛋白 A-I 介导的胆固醇流出。这些结果表明，1 通过激活 LXRα 和 PPARγ 增加 ABCA1 的表达，从而促进载脂蛋白 A-I 介导的巨噬细胞内胆固醇流出。
