Fenofibrate increases HDL-cholesterol by reducing cholesteryl ester transfer protein expression.
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.
van der Hoogt
Caroline C
CC
Netherlands Organization for Applied Scientific Research-Quality of Life, Gaubius Laboratory, 2301 CE Leiden, The Netherlands.
de Haan
Willeke
W
Westerterp
Marit
M
Hoekstra
Menno
M
Dallinga-Thie
Geesje M
GM
Romijn
Johannes A
JA
Princen
Hans M G
HM
Jukema
J Wouter
JW
Havekes
Louis M
LM
Rensen
Patrick C N
PC
D000818:Animals; D001055:Apolipoproteins B / Q000097:blood; D053480:Cholesterol Ester Transfer Proteins / Q000235:genetics / Q000378:metabolism*; D002788:Cholesterol Esters / Q000097:blood / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood*; D011345:Fenofibrate / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000378:metabolism
D001055:Apolipoproteins B; C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D002788:Cholesterol Esters; D008076:Cholesterol, HDL; D000960:Hypolipidemic Agents; D012333:RNA, Messenger; D011345:Fenofibrate