Atorvastatin increases HDL cholesterol by reducing CETP expression in cholesterol-fed APOE*3-Leiden.CETP mice.
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.


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.
de Haan
Willeke
W
Netherlands Organization for Applied Scientific Research-Quality of Life, Gaubius Laboratory, P.O. Box 2215, 2301 CE Leiden, The Netherlands. W.de_Haan.ENDO@lumc.nl
van der Hoogt
Caroline C
CC
Westerterp
Marit
M
Hoekstra
Menno
M
Dallinga-Thie
Geesje M
GM
Princen
Hans M G
HM
Romijn
Johannes A
JA
Jukema
J Wouter
JW
Havekes
Louis M
LM
Rensen
Patrick C N
PC
D000818:Animals; D053318:Apolipoprotein E3 / Q000235:genetics; D000069059:Atorvastatin; D053480:Cholesterol Ester Transfer Proteins / Q000097:blood / Q000235:genetics*; D002791:Cholesterol, Dietary / Q000494:pharmacology; D008076:Cholesterol, HDL / Q000378:metabolism*; D015243:Cholesterol, VLDL / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006937:Hypercholesterolemia / Q000188:drug therapy* / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011758:Pyrroles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism
D053318:Apolipoprotein E3; C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D002791:Cholesterol, Dietary; D008076:Cholesterol, HDL; D015243:Cholesterol, VLDL; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D012333:RNA, Messenger; D000069059:Atorvastatin