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PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORα (PPARα) AGONISTS DIFFERENTIALLY REGULATE INHIBITOR OF DNA BINDING (ID2) EXPRESSION IN RODENTS AND HUMAN CELLS
Citation:
del Carmen Gonzalez, M., C. Corton, N. Acero, D. Munoz-Mingarro, Y. Quiros, J. Alvarez-Millan, E. Herrera, AND C. Bocos. PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORα (PPARα) AGONISTS DIFFERENTIALLY REGULATE INHIBITOR OF DNA BINDING (ID2) EXPRESSION IN RODENTS AND HUMAN CELLS. PPAR research. Hindawi Publishing Corporation, New York, NY, 2012(483536):1-9, (2012).
Impact/Purpose:
The study highlights the potential involvement of the gene Id2 in mediating a number of effects of PPARalpha agonists, including those that may be involved in liver cancer in rodents. The fact that the gene exhibits opposite regulation in rodents and in a human hepatocyte cell line further reinforces the species differences in responses to PPARalpha agnoists.
Description:
Abstract Inhibitor of DNA binding (Id2) is a member of the helix-loop-helix (HLH) transcription factor family whose members play important roles 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 vascular smooth muscle cells thus linking Id2 proteins to altered insulin signalling and glucose metabolism. We hypothesized that PPARα activators may also alter Id2 expression and activity. We demonstrate that PPARα agonists including fibrates are able to regulate Id2 expression. Fenofibrate diminished hepatic Id2 expression in both late pregnant and unmated rats. In rats fasted for 24 hours, hepatic Id2 expression was decreased under conditions known to activate PPARα. In order to determine whether the fibrate effects were mediated by PPARα, wild-type mice and PPARα-null mice were treated with Wy-14,643 (WY) or the plasticizer di-2-ethylhexyl phthalate (DEHP). WY, but not DEHP, reduced Id2 expression in the livers of wild-type mice without an effect in PPARα-null mice. In contrast, fenofibrate induced Id2 expression after 24 hours of treatment in human hepatocarcinoma cells (HepG2). MK-886, a PPARα antagonist, did not block fenofibrate-induced activation of Id2 expression, suggesting a PPARα-independent effect was involved. These findings confirm that Id2 is a gene responsive to PPARα agonists. Like other genes (apoA-I, apoA-V), the opposite directional transcriptional effect in rodents and a human cell line further emphasizes that PPARα agonists have different effects in rodents and humans. Key words: PPARα; Fibrates; Id2; Rodents; Human cells.