de Haan Willeke, van der Hoogt Caroline C, Westerterp Marit, Hoekstra Menno, Dallinga-Thie Geesje M, Princen Hans M G, Romijn Johannes A, Jukema J Wouter, Havekes Louis M, Rensen Patrick C N
Netherlands Organization for Applied Scientific Research-Quality of Life, Gaubius Laboratory, P.O. Box 2215, 2301 CE Leiden, The Netherlands.
Atherosclerosis. 2008 Mar;197(1):57-63. doi: 10.1016/j.atherosclerosis.2007.08.001. Epub 2007 Sep 14.
In addition to lowering low-density lipoprotein (LDL)-cholesterol, statins modestly increase high-density lipoprotein (HDL)-cholesterol in humans and decrease cholesteryl ester transfer protein (CETP) mass and activity. Our aim was to determine whether the increase in HDL depends on CETP expression.
APOE*3-Leiden (E3L) mice, with a human-like lipoprotein profile and a human-like responsiveness to statin treatment, were crossbred with mice expressing human CETP under control of its natural flanking regions resulting in E3L.CETP mice. E3L and E3L.CETP mice were fed a Western-type diet with or without atorvastatin. Atorvastatin (0.01% in the diet) reduced plasma cholesterol in both E3L and E3L.CETP mice (-26 and -33%, P<0.05), mainly in VLDL, but increased HDL-cholesterol only in E3L.CETP mice (+52%). Hepatic mRNA expression levels of genes involved in HDL metabolism, such as phospholipid transfer protein (Pltp), ATP-binding cassette transporter A1 (Abca1), scavenger receptor class B type I (Sr-b1), and apolipoprotein AI (Apoa1), were not differently affected by atorvastatin in E3L.CETP mice as compared to E3L mice. However, in E3L.CETP mice, atorvastatin down-regulated the hepatic CETP mRNA expression (-57%; P<0.01) as well as the total CETP level (-29%) and cholesteryl esters (CE) transfer activity (-36%; P<0.05) in plasma.
Atorvastatin increases HDL-cholesterol in E3L.CETP mice by reducing the CETP-dependent transfer of cholesterol from HDL to (V)LDL, as related to lower hepatic CETP expression and a reduced plasma (V)LDL pool.
除降低低密度脂蛋白（LDL）胆固醇外，他汀类药物还可适度增加人体高密度脂蛋白（HDL）胆固醇，并降低胆固醇酯转运蛋白（CETP）的量和活性。我们的目的是确定HDL的增加是否依赖于CETP的表达。
将具有类人脂蛋白谱和对他汀类药物治疗具有类人反应性的载脂蛋白E3-莱顿（APOE3-Leiden，E3L）小鼠与在其天然侧翼区域控制下表达人CETP的小鼠杂交，产生E3L.CETP小鼠。给E3L和E3L.CETP小鼠喂食含或不含阿托伐他汀的西式饮食。阿托伐他汀（饮食中含0.01%）降低了E3L和E3L.CETP小鼠的血浆胆固醇（分别降低26%和33%，P<0.05），主要降低极低密度脂蛋白（VLDL）中的胆固醇，但仅在E3L.CETP小鼠中增加了HDL胆固醇（增加52%）。与E3L小鼠相比，阿托伐他汀对E3L.CETP小鼠中参与HDL代谢的基因，如磷脂转运蛋白（Pltp）、ATP结合盒转运体A1（Abca1）、B类I型清道夫受体（Sr-b1）和载脂蛋白AI（Apoa1）的肝脏mRNA表达水平没有不同影响。然而，在E3L.CETP小鼠中，阿托伐他汀下调了肝脏CETP mRNA表达（降低57%；P<0.01）以及血浆中的总CETP水平（降低29%）和胆固醇酯（CE）转移活性（降低36%；P<0.05）。
阿托伐他汀通过降低CETP依赖性的胆固醇从HDL向（V）LDL的转移，增加了E3L.CETP小鼠的HDL胆固醇，这与肝脏CETP表达降低和血浆（V）LDL池减少有关。
