Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Hokkaido University, Kita-ku, Japan.
Eur J Pharmacol. 2011 Jul 15;662(1-3):9-14. doi: 10.1016/j.ejphar.2011.04.043. Epub 2011 May 1.
ATP-binding cassette transporter A1 (ABCA1) is predicted to be involved in the control of apolipoprotein AI-mediated cholesterol efflux: biosynthesis of high-density lipoprotein (HDL). However, the effects of HMG-CoA reductase inhibitors (statins) on ABCA1 in the liver and the precise mechanisms of their actions have been obscure. The aims of this study were to determine whether statins (atorvastatin (Ato) and pitavastatin (Pit)) affect hepatic ABCA1 expression and to clarify the mechanisms of their actions using HepG2 cells and the rat liver. We examined alterations in mRNA and protein levels of ABCA1 and peroxisome proliferator-activated receptors (PPARs) by quantitative real-time polymerase chain reaction (PCR) and Western blot analysis, respectively. In vitro and in vivo studies suggested that Pit increases ABCA1 mRNA level, but not Ato. Pit greatly increased Abca1 mRNA level and also increased the amount of plasma HDL and the mRNA level of PPARα. Clofibrate (PPARα agonist) increased ABCA1 expression in HepG2 cells and rat primary hepatocytes more than did PPAR β/δ and γ agonists. Pit-induced ABCA1 expression alteration was blocked by GW6471 (PPARα antagonist) and by PPARα knockdown. In this study, we demonstrated that Pit affect ABCA1 expression via PPARα in hepatocytes. The strategy to target a PPARα agonist in the liver can lead to increases in ABCA1 expression and HDL level.
三磷酸腺苷结合盒转运体 A1（ABCA1）被预测参与载脂蛋白 AI 介导的胆固醇流出的控制：高密度脂蛋白（HDL）的生物合成。然而，HMG-CoA 还原酶抑制剂（他汀类药物）对肝脏中 ABCA1 的影响及其确切作用机制一直不清楚。本研究旨在确定他汀类药物（阿托伐他汀（Ato）和匹伐他汀（Pit））是否影响肝 ABCA1 表达，并使用 HepG2 细胞和大鼠肝脏阐明其作用机制。我们通过定量实时聚合酶链反应（PCR）和 Western blot 分析分别检查了 ABCA1 和过氧化物酶体增殖物激活受体（PPARs）的 mRNA 和蛋白水平的变化。体外和体内研究表明，Pit 增加了 ABCA1 mRNA 水平，但 Ato 没有。Pit 极大地增加了 Abca1 mRNA 水平，同时也增加了血浆 HDL 水平和 PPARα 的 mRNA 水平。氯贝特（PPARα 激动剂）在 HepG2 细胞和大鼠原代肝细胞中增加 ABCA1 表达的程度高于 PPARβ/δ 和γ 激动剂。Pit 诱导的 ABCA1 表达改变被 GW6471（PPARα 拮抗剂）和 PPARα 敲低所阻断。在这项研究中，我们证明了 Pit 通过 PPARα 在肝细胞中影响 ABCA1 表达。靶向肝脏中 PPARα 激动剂的策略可以导致 ABCA1 表达和 HDL 水平增加。
