on December 23, 2004
Published online before print December 23, 2004, doi: 10.1161/01.ATV.0000154140.73570.00
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Submitted on July 15, 2004
Accepted on November 19, 2004
Regulation of Human ApoA-I by Gemfibrozil and Fenofibrate Through Selective Peroxisome Proliferator-Activated Receptor 
Modulation
Hélène Duez *;
From UR.545INSERM, Département d’Athérosclérose (H.D., P.P., I.P.T., F.P., G.L., J.-C.F., C.F., B.S.), Institut Pasteur Lille and Faculté de Pharmacie, Université de Lille2, France; UR.459INSERM, Biologie Moléculaire des Récepteurs Nucléaires (B.L., P.L.), Faculté de Médecine Lille, France; the Department of Veterinary Science (J.M.P.), Center for Molecular Toxicology, Pennsylvania State University, Hershey, Penn; the Laboratory of Metabolism (F.J.G.), National Cancer Institute, National Institute of Health, Bethesda, Md; and GENFIT.SA (R.G., S.H.), Loos, France.
* To whom correspondence should be addressed. E-mail: helene.duez{at}pasteur-lille.fr.
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) 
-/- mice demonstrated that PPAR 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 did GF in hA-ITgPPAR+/+ mice, both fibrates induced acylCoAoxidase mRNA similarly. FF and GF transactivated PPAR 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 PPAR. 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.
Key words: apolipoprotein A-I • high-density lipoprotein • fibrates • peroxisome proliferator-activated receptor
•
selective PPAR modulator
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