Title
Atorvastatin increases HDL cholesterol by reducing CETP expression in cholesterol-fed APOE*3-Leiden.CETP mice
Author
de Haan, W.
van der Hoogt, C.C.
Westerterp, M.
Hoekstra, M.
Dallinga-Thie, G.M.
Princen, H.M.G.
Romijn, J.A.
Jukema, J.W.
Havekes, L.M.
Rensen, P.C.N.
TNO Kwaliteit van Leven
Publication year
2008
Abstract
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. © 2007 Elsevier Ireland Ltd. All rights reserved.
Subject
Health
CETP
High-density lipoprotein
HMGCoA reductase
Statin
Transgenic mice
ABC transporter A1
apolipoprotein A1
apolipoprotein E3
atorvastatin
cholesterol ester transfer protein
high density lipoprotein
high density lipoprotein cholesterol
messenger RNA
phospholipid transfer protein
scavenger receptor BI
very low density lipoprotein
very low density lipoprotein cholesterol
animal experiment
animal model
article
cholesterol blood level
cholesterol diet
controlled study
drug effect
gene expression
hypercholesterolemia
lipoprotein blood level
lipoprotein metabolism
male
mouse
nonhuman
priority journal
protein expression
transgenic mouse
Animals
Apolipoprotein E3
Cholesterol Ester Transfer Proteins
Cholesterol, Dietary
Cholesterol, HDL
Cholesterol, VLDL
Dose-Response Relationship, Drug
Female
Gene Expression
Heptanoic Acids
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Hypercholesterolemia
Liver
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Pyrroles
RNA, Messenger
To reference this document use:
http://resolver.tudelft.nl/uuid:b1f12e01-d3a5-45f5-9333-01c50d94ab73
DOI
https://doi.org/10.1016/j.atherosclerosis.2007.08.001
TNO identifier
240676
ISSN
0021-9150
Source
Atherosclerosis, 197 (1), 57-63
Document type
article