Molecular Mechanisms of Quercetin-Induced ATP-Binding Cassette Transporter A1 Expression in Macrophages

• Main Authors: Yu-Cheng Chang, 張育誠
• Other Authors: An-Na Chiang
• Format: Others
• Language: zh-TW
• Published: 2013
• Online Access: http://ndltd.ncl.edu.tw/handle/77899938086330162328

博士 === 國立陽明大學 === 生化暨分子生物研究所 === 101 === ATP-binding cassette transporter A1 (ABCA1) plays a crucial role in exporting out cholesterol from macrophages, a function relevant to its involvement in the prevention of atherosclerosis. Quercetin, one of flavonoids, has been described to reduce oxidative and inflammatory processes. This study aims to investigate the effect of quercetin on regulation of ABCA1 expression and its underlying mechanisms in macrophages. The results show that quercetin markedly enhanced cholesterol efflux from macrophages in a concentration-dependent manner, which was associated with an increase in ABCA1 mRNA and protein expression. Remarkably, quercetin is able to stimulate the phosphorylation of p38 by up to 234-fold at 6 h via an activation of the transforming growth factor β-activated kinase 1 (TAK1) and mitogen-activated kinase kinase 3/6 (MKK3/6). Inhibition of p38 with a pharmacological inhibitor or small hairpin RNA (shRNA) suppressed the stimulatory effects of quercetin on ABCA1 expression and cholesterol efflux. Moreover, knockdown of p38 reduced quercetin-enhanced ABCA1 promoter activity and the binding of specificity protein 1 (Sp1) and liver X receptor α (LXRα) to the ABCA1 promoter using chromatin immunoprecipitation assays. An elevation in blood glucose concentration leads to increased risk of developing diabetes-associated atherosclerotic cardiovascular disease due to an excessive accumulation of cholesterol in arterial macrophages. The present study also aims to investigate the effect of hyperglycemia on the regulation of ABCA1 expression and its underlying mechanisms. Our results show that high glucose activates the extracellular signal-regulated kinases (ERK) signaling pathway via reactive oxygen species (ROS) production, which in turn down-regulates ABCA1 mRNA and protein expression. This down-regulation is mediated by accelerating ABCA1 mRNA degradation in macrophages exposed to high concentrations of glucose. Taken together, these results provide the mechanisms by which quercetin and hyperglycemia regulate ABCA1 expression and cholesterol efflux in macrophages, suggesting promising strategies for the treatment of diabetes-associated atherosclerosis.