FUNCTIONAL INTERACTIONS OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR, RETINOID-X RECEPTOR, AND SP1 IN THE TRANSCRIPTIONAL REGULATION OF THE ACYL-COENZYME-A OXIDASE PROMOTER

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily. For transcriptional activation of their target genes, PPARs heterodimerize with the retinoid-X receptor (RXR) . The convergence of the PPAR and RXR signaling pathways has been show n to have an important function in lipid metabolism. The promoter of t he gene encoding the acyl-coenzyme-A oxidase (ACO), the rate-limiting enzyme in peroxisomal beta-oxidation of fatty acids, is a target site of PPAR action. In this study, we examined the role and the contributi on of both cis- and trans-acting factors in the transcriptional regula tion of this gene using transient transfections in insect cells. We id entified several functional cis-acting elements present in the promote r of the ACO gene and established that PPAR-dependent as well as PPAR- independent mechanisms can activate the ACO promoter in these cells. W e show that the PPAR/RXR heterodimer exerts its effect through two res ponse elements within the ACO promoter, in synergy with the transcript ion factor Sp1 via five Sp1-binding sites. Furthermore, this functiona l interaction also occurs when Sp1 is coexpressed with PPAR or RXR alo ne, indicating that activation can occur independently of PPAR/RXR het erodimers.