Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Life Science Research Center, University of South China, Hengyang 421001, P.R. China.
Int J Mol Med. 2012 May;29(5):946-56. doi: 10.3892/ijmm.2012.924. Epub 2012 Feb 21.
The ATP-binding membrane cassette transporter A1 (ABCA1) plays a protective role in the development of atherosclerosis for the reverse cholesterol transport process. Epigallocatechin-3-gallate (EGCG), which exists abundantly in green tea, exerts an anti-atherosclerotic effect via anti-inflammatory and metabolic regulation activities. Many genes and proteins related to lipid metabolism are involved in the lowering cholesterol effects of EGCG. However, effects of EGCG on ABCA1 have rarely been described. In the study presented here, we found that exposure of macrophage foam cells to TNF-α results in a downregulation of ABCA1 and a decrease in cholesterol efflux to apoA1, which is attenuated by pretreatment with EGCG. Moreover, rather than activating the Liver X receptor (LXR) pathway, inhibition of the TNF-α-induced nuclear factor-κB (NF-κB) activity is detected with EGCG treatment in cells. In order to inhibit the NF-κB activity, EGCG can promote the dissociation of the nuclear factor E2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1) complex; when the released Nrf2 translocates to the nucleus and activates the transcription of genes containing an ARE element inhibition of NF-κB occurs and Keap1 is separated from the complex to directly interact with IKKβ and thus represses NF-κB function. These results provide novel insight into the anti-inflammatory effects of EGCG, as well as the identification of a novel potential therapeutic role for the prevention of atherosclerosis.
三磷酸腺苷结合膜盒转运体 A1（ABCA1）在胆固醇逆转运过程中对动脉粥样硬化的发生起保护作用。表没食子儿茶素没食子酸酯（EGCG）大量存在于绿茶中，通过抗炎和代谢调节作用发挥抗动脉粥样硬化作用。许多与脂质代谢相关的基因和蛋白质参与 EGCG 降低胆固醇的作用。然而，EGCG 对 ABCA1 的影响很少被描述。在本研究中，我们发现巨噬细胞泡沫细胞暴露于 TNF-α会导致 ABCA1 下调，胆固醇向载脂蛋白 A1 的流出减少，而 EGCG 预处理可减弱这种减少。此外，与激活肝 X 受体（LXR）途径相反，用 EGCG 处理细胞时会检测到抑制 TNF-α诱导的核因子-κB（NF-κB）活性。为了抑制 NF-κB 活性，EGCG 可以促进核因子 E2 相关因子 2（Nrf2）-Kelch 样 ECH 相关蛋白 1（Keap1）复合物的解离；当释放的 Nrf2 易位到细胞核并激活含有 ARE 元件的基因转录时，会抑制 NF-κB 的发生，并且 Keap1 与复合物分离，直接与 IKKβ相互作用，从而抑制 NF-κB 功能。这些结果为 EGCG 的抗炎作用提供了新的见解，并确定了预防动脉粥样硬化的新的潜在治疗作用。
