Millar John S, Brousseau Margaret E, Diffenderfer Margaret R, Barrett P Hugh R, Welty Francine K, Cohn Jeffrey S, Wilson Aisha, Wolfe Megan L, Nartsupha Chorthip, Schaefer Peter M, Digenio Andres G, Mancuso James P, Dolnikowski Gregory G, Schaefer Ernst J, Rader Daniel J
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
J Lipid Res. 2008 Mar;49(3):543-9. doi: 10.1194/jlr.M700268-JLR200. Epub 2007 Nov 21.
Cholesteryl ester transfer protein (CETP) inhibition leads to changes in lipoprotein metabolism. We studied the effect of the CETP inhibitor torcetrapib on VLDL apolipoprotein E (apoE) metabolism. Subjects, pretreated with atorvastatin (n = 9) or untreated (n = 10), received placebo followed by torcetrapib (4 weeks each). After each treatment, subjects underwent a primed-constant infusion of D(3)-leucine to determine the VLDL apoE production rate (PR) and fractional catabolic rate (FCR). Torcetrapib alone reduced the VLDL apoE pool size (PS) (-28%) by increasing the VLDL apoE FCR (77%) and leaving the VLDL apoE PR unchanged. In subjects pretreated with atorvastatin, torcetrapib increased the VLDL apoE FCR (25%) and PR (21%). This left the VLDL apoE PS unchanged but increased the VLDL apoE content, likely enhancing VLDL clearance and reducing LDL production in this group. Used alone, torcetrapib reduces the VLDL apoE PS by increasing the apoE FCR while leaving the VLDL apoE content unchanged. In contrast, torcetrapib added to atorvastatin treatment increases both the VLDL apoE FCR and PR, leaving the VLDL apoE PS unchanged. Adding torcetrapib to atorvastatin treatment increases the VLDL apoE content, likely leading to decreased conversion of VLDL to LDL, reduced LDL production, and lower levels of circulating VLDL and LDL.
胆固醇酯转运蛋白（CETP）抑制会导致脂蛋白代谢发生变化。我们研究了CETP抑制剂托彻普贝对极低密度脂蛋白载脂蛋白E（apoE）代谢的影响。先用阿托伐他汀预处理的受试者（n = 9）或未接受治疗的受试者（n = 10），先接受安慰剂，然后接受托彻普贝治疗（各4周）。每次治疗后，受试者接受D(3)-亮氨酸的首剂-持续输注，以确定极低密度脂蛋白apoE的生成率（PR）和分数分解代谢率（FCR）。单独使用托彻普贝可通过提高极低密度脂蛋白apoE的FCR（77%）并使极低密度脂蛋白apoE的PR保持不变，从而降低极低密度脂蛋白apoE池大小（PS）（-28%）。在先用阿托伐他汀预处理的受试者中，托彻普贝可提高极低密度脂蛋白apoE的FCR（25%）和PR（21%）。这使得极低密度脂蛋白apoE的PS保持不变，但增加了极低密度脂蛋白apoE的含量，可能增强了该组的极低密度脂蛋白清除并减少了低密度脂蛋白的生成。单独使用时，托彻普贝通过提高apoE的FCR来降低极低密度脂蛋白apoE的PS，同时使极低密度脂蛋白apoE的含量保持不变。相比之下，在阿托伐他汀治疗中添加托彻普贝可同时提高极低密度脂蛋白apoE的FCR和PR，使极低密度脂蛋白apoE的PS保持不变。在阿托伐他汀治疗中添加托彻普贝会增加极低密度脂蛋白apoE的含量，可能导致极低密度脂蛋白向低密度脂蛋白的转化减少、低密度脂蛋白生成减少以及循环中的极低密度脂蛋白和低密度脂蛋白水平降低。
