Fenofibrate increases HDL cholesterol by reducing cholesteryl ester transfer protein expression

Caroline C. Van der Hoogt, Willeke De Haan, Marit Westerterp, Menno Hoekstra, Geesje M. Dallinga-Thie, Johannes A. Romijn, Hans M..G. Princen, J. Wouter Jukema, Louis M. Havekes, and Patrick C. N. Rensen

Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, Zuid-Holland 2300 RC

Corresponding Author: P.C.N.Rensen{at}lumc.nl

In addition to efficiently lowering VLDL-triglycerides (TG), 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). Hereto, APOE*3-Leiden (E3L) transgenic mice without and with the human CETP transgene, under 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-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 as compared to 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.

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