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

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.