Objective: 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. Methods and results: 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. Conclusions: 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.

CETP, HMGCoA reductase, High-density lipoprotein, Statin, Transgenic mice
dx.doi.org/10.1016/j.atherosclerosis.2007.08.001, hdl.handle.net/1765/28972
Atherosclerosis
Erasmus MC: University Medical Center Rotterdam

de Haan, W, van der Hoogt, C.C, Westerterp, M, Hoekstra, M, Dallinga-Thie, G.M, Princen, H.M.G, … Rensen, P.C.N. (2008). Atorvastatin increases HDL cholesterol by reducing CETP expression in cholesterol-fed APOE*3-Leiden.CETP mice. Atherosclerosis, 197(1), 57–63. doi:10.1016/j.atherosclerosis.2007.08.001