Peroxisome Proliferator-Activated ReceptorαAgonists Differentially Regulate Inhibitor of DNA Binding Expression in Rodents and Human Cells

Inhibitor of DNA binding (Id2) is a helix-loop-helix (HLH) transcription factor that participates in cell differentiation and proliferation. Id2 has been linked to the development of cardiovascular diseases since thiazolidinediones, antidiabetic agents and peroxisome proliferator-activated receptor (PPAR) gamma agonists, have been reported to diminish Id2 expression in human cells. We hypothesized that PPAR α activators may also alter Id2 expression. Fenofibrate diminished hepatic Id2 expression in both late pregnant and unmated rats. In 24 hour fasted rats, Id2 expression was decreased under conditions known to activate PPAR α . In order to determine whether the fibrate effects were mediated by PPAR α , wild-type mice and PPAR α -null mice were treated with Wy-14,643 (WY). WY reduced Id2 expression in wild-type mice without an effect in PPAR α -null mice. In contrast, fenofibrate induced Id2 expression after 24 hours of treatment in human hepatocarcinoma cells (HepG2). MK-886, a PPAR α antagonist, did not block fenofibrate-induced activation of Id2 expression, suggesting a PPAR α -independent effect was involved. These findings confirm that Id2 is a gene responsive to PPAR α agonists. Like other genes (apolipoprotein A-I, apolipoprotein A-V), the opposite directional transcriptional effect in rodents and a human cell line further emphasizes that PPAR α agonists have different effects in rodents and humans.