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  • Title: Regulation of human apoA-I by gemfibrozil and fenofibrate through selective peroxisome proliferator-activated receptor alpha modulation.
    Author: Duez H, Lefebvre B, Poulain P, Torra IP, Percevault F, Luc G, Peters JM, Gonzalez FJ, Gineste R, Helleboid S, Dzavik V, Fruchart JC, Fiévet C, Lefebvre P, Staels B.
    Journal: Arterioscler Thromb Vasc Biol; 2005 Mar; 25(3):585-91. PubMed ID: 15618549.
    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 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.
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