Regulation of human ApoA-I by gemfibrozil and fenofibrate through selective peroxisome proliferator-activated receptor α modulation

Hélène Duez, Bruno Lefebvre, Philippe Poulain, Inés Pineda Torra, Frédéric Percevault, Gérald Luc, Jeffrey M. Peters, Frank J. Gonzalez, Romain Gineste, Stéphane Helleboid, Vladimir Dzavik, Jean Charles Fruchart, Catherine Fiévet, Philippe Lefebvre, Bart Staels

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108 Scopus citations

Abstract

Objective - The objective of this trial was to study the effects of fenofibrate (FF) and gemfibrozil (GF), the most commonly used fibrates, on high-density lipoprotein (HDL) and apolipoprotein (apo) A-I. Methods and Results - In a head-to-head double-blind clinical trial, both FF and GF decreased triglycérides and increased HDL cholesterol levels to a similar extent, whereas plasma apoA-I only increased after FF but not GF. Results in human (h) apoA-Itransgenic (hA-ITg) peroxisome proliferator-activated receptor (PPAR) α-/- mice demonstrated that PPARa mediates the effects of FF and GF on HDL in vivo. Although plasma and hepatic mRNA levels of hapoA-I increased more pronouncedly after FF than GF in hA-ITgPPARα+/+ mice, both fibrates induced acylCoAoxidase mRNA similarly. FF and GF transactivated PPARα with similar activity and affinity on a DR-1 PPAR response element, but maximal activation on the hapoA-I DR-2 PPAR response element was significantly lower for GF than for FF. Moreover, GF induced recruitment of the coactivator DRIP205 on the DR-2 site less efficiently than did FF. Conclusion - Both GF and FF exert their effects on HDL through PPARα. Whereas FF behaves as a full agonist, GF appears to act as a partial agonist due to a differential recruitment of coactivators to the promoter. These observations provide an explanation for the differences in the activity of these fibrates on apoA-I.

Original languageEnglish (US)
Pages (from-to)585-591
Number of pages7
JournalArteriosclerosis, thrombosis, and vascular biology
Volume25
Issue number3
DOIs
StatePublished - Mar 2005

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

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