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


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.
Duez
Hélène
H
UR545INSERM, Département d'Athérosclérose, Institut Pasteur Lille and Faculté de Pharmacie, Université de Lille2, France. helene.duez@pasteur-lille.fr
Lefebvre
Bruno
B
Poulain
Philippe
P
Torra
Inés Pineda
IP
Percevault
Frédéric
F
Luc
Gérald
G
Peters
Jeffrey M
JM
Gonzalez
Frank J
FJ
Gineste
Romain
R
Helleboid
Stéphane
S
Dzavik
Vladimir
V
Fruchart
Jean-Charles
JC
Fiévet
Catherine
C
Lefebvre
Philippe
P
Staels
Bart
B
D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D016632:Apolipoprotein A-I / Q000097:blood* / Q000235:genetics; D008076:Cholesterol, HDL / Q000097:blood; D005260:Female; D011345:Fenofibrate / Q000008:administration & dosage*; D015248:Gemfibrozil / Q000008:administration & dosage*; D006801:Humans; D006949:Hyperlipidemias / Q000188:drug therapy* / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000008:administration & dosage*; D008099:Liver / Q000502:physiology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D013045:Species Specificity; D014280:Triglycerides / Q000097:blood
D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D000960:Hypolipidemic Agents; D047493:PPAR alpha; D012333:RNA, Messenger; D014280:Triglycerides; D015248:Gemfibrozil; D011345:Fenofibrate