Peroxisomal proliferator activated receptor alpha (PPARalpha) is activated by fibrate drugs which are known to protect against atherosclerosis. The present study examines the effects of PPARalpha on SR-BI expression. For this study, a rat SR-BI promoter-luciferase reporter gene construct was co-transfected into different cell lines with expression vectors that encode for PPARalpha+/-retinoic X receptor alpha (RXRalpha). PPARalpha/RXR increased the activity of the SR-BI promoter, an effect that was enhanced by clofibrate. Sequence analysis of the rat SR-BI promoter revealed the presence of a putative peroxisomal proliferator response element (PPRE) at bp -1,622. Electrophoretic mobility shift assays demonstrated that PPARalpha and RXRalpha are able to bind to the SR-BI PPRE motif. In addition, mutational analysis studies confirmed that this PPRE motif is responsible for the PPARalpha/RXRalpha-dependent activation of the rat SR-BI promoter in the cell lines examined.