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

Area of Science:

• Cardiovascular Research
• Metabolic Syndrome
• Pharmacology

Background:

• Fenofibrate effectively lowers VLDL-triglycerides (TGs) and increases HDL-cholesterol in humans.
• The mechanism by which fenofibrate raises HDL-cholesterol, specifically its dependence on cholesteryl ester transfer protein (CETP), requires elucidation.

Purpose of the Study:

• To investigate whether the HDL-cholesterol-raising effect of fenofibrate is mediated by CETP.
• To explore the impact of fenofibrate on CETP expression and activity in a relevant animal model.

Main Methods:

• Utilized APOE*3-Leiden (E3L) transgenic mice with and without the human CETP transgene.
• Administered fenofibrate via a Western-type diet and analyzed plasma lipids, HDL-cholesteryl ester turnover, and hepatic gene expression.
• Measured CETP mRNA levels and cholesteryl ester transfer activity in plasma.

Main Results:

• Fenofibrate significantly reduced plasma TGs and VLDL in both E3L and E3L.CETP mice.
• Fenofibrate did not alter HDL-cholesterol in E3L mice but dose-dependently increased it in E3L.CETP mice (up to +91%).
• Fenofibrate decreased hepatic CETP mRNA and plasma CETP activity in E3L.CETP mice without affecting HDL-cholesterol turnover.

Conclusions:

• Fenofibrate increases HDL-cholesterol by inhibiting CETP-mediated transfer of cholesteryl esters from HDL to VLDL.
• This mechanism involves reduced hepatic CETP expression and a smaller plasma VLDL pool.
• The findings highlight CETP as a key mediator of fenofibrate's beneficial effects on HDL-cholesterol levels.