DIVERSE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS BIND TO THE PEROXISOME PROLIFERATOR-RESPONSIVE ELEMENTS OF THE RAT HYDRATASE DEHYDROGENASE AND FATTY ACYL-COA OXIDASE GENES BUT DIFFERENTIALLY INDUCE EXPRESSION

The ability of peroxisome proliferator-activated receptors (PPARs) to induce expression of a reporter gene linked to a peroxisome proliferat or-responsive element (PPRE) from either the rat enoyl-CoA hydratase/3 -hydroxyacyl-CoA dehydrogenase gene or acyl-CoA oxidase [acyl-CoA: oxy gen 2-oxidoreductase, EC 1.3.3.6] gene was examined by transient trans fection assays in COS cells. Mouse and rat PPARs, as well as Xenopus P PARalpha (xPPARalpha) could induce expression of a reporter gene linke d to the hydratase/dehydrogenase PPRE in the presence of the peroxisom e proliferators ciprofibrate or Wy-14,643, whereas xPPARbeta and xPPAR gamma were ineffective. A similar induction of expression of a reporte r gene linked to the acyl-CoA oxidase PPRE was observed with all PPARs except xPPARbeta. Extracts from cells transfected with PPAR-encoding genes contained factors that bound to both PPREs. In vitro synthesized PPARs could interact weakly with both PPREs; however, binding of each PPAR to both PPREs was significantly increased by the addition of COS cell nuclear extracts, demonstrating that efficient PPAR/DNA binding requires auxiliary cofactors. One cofactor was identified as the 9-cis -retinoic acid receptor, RXRalpha (retinoid X receptor alpha). Coopera tive DNA binding and heteromerization between RXRalpha and each of the PPARs could be seen with both PPREs. Our results demonstrate that PPA R/PPRE binding and cooperativity with RXRalpha (and other cofactors) a re obligatory but not necessarily sufficient for peroxisome proliferat or-dependent transcription induction and that distinct PPREs can selec tively mediate induction by particular PPARs.