Fibrates Increase Human REV-ERBα Expression in Liver via a Novel Peroxisome Proliferator-Activated Receptor Response Element

Fibrates are widely used hypolipidemic drugs that act by modulating the expression of genes involved in lipid and lipoprotein metabolism. Whereas the activation of gene transcription by fibrates occurs via the nuclear receptor peroxisome proliferator-activated receptor-α (PPARα) interacting with response elements consisting of a direct repeat of the AGGTCA motif spaced by one nucleotide (DR1), the mechanisms of negative gene regulation by fibrates and PPARα are largely unknown. In the present study, we demonstrate that fibrates induce the expression of the nuclear receptor Rev-erbα, a negative regulator of gene transcription. Fibrates increase Rev-erbα mRNA levels both in primary human hepatocytes and in HepG2 hepatoblastoma cells. In HepG2 cells, fibrates furthermore induce Rev-erbα protein synthesis rates. Transfection studies with reporter constructs driven by the human Rev-erbα promoter revealed that fibrates induce Rev-erbα expression at the transcriptional level via PPARα. Site-directed mutagenesis ...