Regulation of human apoA-I by gemfibrozil and fenofibrate through selective peroxisome proliferator-activated receptor alpha modulation.

Author(s): Duez H, Lefebvre B, Poulain P, Torra IP, Percevault F, Luc G, Peters JM, Gonzalez FJ, Gineste R, Helleboid S, Dzavik V, Fruchart JC, Fievet C, Lefebvre P, Staels B

Affiliation(s): UR545INSERM, Departement d'Atherosclerose, Institut Pasteur Lille and Faculte de Pharmacie, Universite de Lille2, France. helene.duez@pasteur-lille.fr

Publication date & source: 2005-03, Arterioscler Thromb Vasc Biol., 25(3):585-91. Epub 2004 Dec 23.

Publication type: Clinical Trial; Multicenter Study; Randomized Controlled Trial

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 triglycerides 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) alpha-/- mice demonstrated that PPARalpha 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-ITgPPARalpha+/+ mice, both fibrates induced acylCoAoxidase mRNA similarly. FF and GF transactivated PPARalpha 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. CONCLUSIONS: Both GF and FF exert their effects on HDL through PPARalpha. 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.