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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:585.)
© 2005 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Regulation of Human ApoA-I by Gemfibrozil and Fenofibrate Through Selective Peroxisome Proliferator-Activated Receptor 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

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; GENFIT.SA (R.G., S.H.), Loos, France; and Cardiac Catherization Laboratory & Interventional Cardiology (V.D.), University Health Network, Toronto, Canada.

Correspondence to Hélène Duez or Prof Bart Staels, UR545INSERM, Département d’Athérosclérose, Institut Pasteur Lille, 1 rue Calmette, 59019 Lille, France. E-mail helene.duez{at}pasteur-lille.fr or bart.staels@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 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.

In hyperlipidemic patients and human apolipoprotein A-Itransgenic (hA-ITg) mice, fenofibrate (FF) and gemfibrozil (GF) increase HDL cholesterol, whereas apoA-I levels only increased after FF. Because of differential coactivator recruitment to the promoter, FF and GF, respectively, behave as full and partial PPAR agonists, likely explaining the clinical 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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