Fenofibrate increases HDL-cholesterol by reducing cholesteryl ester transfer protein expression

Fenofibrate increases HDL-cholesterol by reducing cholesteryl ester transfer protein expression

TNO Kwaliteit van Leven
van der Hoogt, C.C.
de Haan, W.
Westerterp, M.
Hoekstra, M.
Dallinga-Thie, G.M.
Romijn, J.A.
Princen, H.M.G.
Jukema, J.W.
Havekes, L.M.
Rensen, P.C.N.

2007

In addition to efficiently decreasing VLDL-triglycerides (TGs), fenofibrate increases HDL-cholesterol levels in humans. We investigated whether the fenofibrate-induced increase in HDL-cholesterol is dependent on the expression of the cholesteryl ester transfer protein (CETP). To this end, APOE*3-Leiden (E3L) transgenic mice without and with the human CETP transgene, under the control of its natural regulatory flanking regions, were fed a Western-type diet with or without fenofibrate. Fenofibrate (0.04% in the diet) decreased plasma TG in E3L and E3L.CETP mice (-59% and -60%; P < 0.001), caused by a strong reduction in VLDL. Whereas fenofibrate did not affect HDL-cholesterol in E3L mice, fenofibrate dose-dependently increased HDL-cholesterol in E3L.CETP mice (up to +91%). Fenofibrate did not affect the turnover of HDL-cholesteryl ester (CE), indicating that fenofibrate causes a higher steady-state HDL-cholesterol level without altering the HDL-cholesterol flux through plasma. Analysis of the hepatic gene expression profile showed that fenofibrate did not differentially affect the main players in HDL metabolism in E3L.CETP mice compared with E3L mice. However, in E3L.CETP mice, fenofibrate reduced hepatic CETP mRNA (-72%; P < 0.01) as well as the CE transfer activity in plasma (-73%; P < 0.01). We conclude that fenofibrate increases HDL-cholesterol 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. Copyright ©2007 by the American Society for Biochemistry and Molecular Biology, Inc.

Biomedical Research
Fibrate
High density lipoprotein
Peroxisome proliferator-activated receptor alpha
Transgenic mice
apolipoprotein E
cholesterol ester transfer protein
fenofibrate
high density lipoprotein cholesterol
very low density lipoprotein
animal experiment
cholesterol transport
controlled study
drug mechanism
food intake
gene expression
lipid metabolism
mouse
nonhuman
priority journal
protein expression
protein function
steady state
transgene
Animals
Antilipemic Agents
Apolipoproteins B
Cholesterol Ester Transfer Proteins
Cholesterol Esters
Cholesterol, HDL
Gene Expression
Humans
Liver
Male
Mice
Mice, Transgenic
Procetofen
RNA, Messenger

http://resolver.tudelft.nl/uuid:8b7ab5ee-d44e-482d-b3f3-cbb6d6e18703

https://doi.org/10.1194/jlr.m700108-jlr200

240111

0022-2275

Journal of Lipid Research, 48 (48), 1763-1771

article