THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR RETINOID-X RECEPTOR HETERODIMER IS ACTIVATED BY FATTY-ACIDS AND FIBRATE HYPOLIPEMIC DRUGS

The peroxisome proliferator-activated receptor (PPAR) is a member of t he steroid hormone receptor superfamily and is activated by a variety of fibrate hypolipidaemic drugs and non-genotoxic rodent hepatocarcino gens that are collectively termed peroxisome proliferators. A key mark er of peroxisome proliferator action is the peroxisomal enzyme acyl Co A oxidase, which is elevated about tenfold in the livers of treated ro dents. We have previously shown that a peroxisome proliferator respons e element (PPRE) is located 570 bp upstream of the rat peroxisomal acy l CoA oxidase gene and that PPAR binds to it. We show here that the re tinoid X receptor (RXR) is required for PPAR to bind to the PPRE, and that the RXR ligand, 9-cis retinoic acid, enhances PPAR action. Retino ids may therefore modulate the action of peroxisome proliferators and PPAR may interfere with retinoid action, perhaps providing one mechani sm to explain the toxicity of peroxisome proliferators. We have also s hown that a variety of hypolipidaemic drugs and fatty acids can activa te PPAR. This supports the suggestion that the physiological role of P PAR is to regulate fatty acid homeostasis, and provides further eviden ce that PPAR is the target of the fibrate class of hypolipidaemic drug s. Finally, we have demonstrated that a metabolically stabilized fatty acid is a potent PPAR activator, suggesting that fatty acids, or thei r acyl CoA derivatives, may be the natural ligands of PPAR.