TARGETED DISRUPTION OF THE ALPHA-ISOFORM OF THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GENE IN MICE RESULTS IN ABOLISHMENT OF THE PLEIOTROPIC EFFECTS OF PEROXISOME PROLIFERATORS

To gain insight into the function of peroxisome proliferator-activated receptor (PPAR) isoforms in rodents, we disrupted the ligand-binding domain of the or isoform of mouse PPAR (mPPAR alpha) by homologous rec ombination. Mice homozygous for the mutation lack expression of mPPAR alpha protein and yet are viable and fertile and exhibit no detectable gross phenotypic defects, Remarkably, these animals do not display th e peroxisome proliferator pleiotropic response when challenged with th e classical peroxisome proliferators, clofibrate and Wy-14,643, Follow ing exposure to these chemicals, hepatomegaly, peroxisome proliferatio n, and transcriptional activation of target genes were not observed. T hese results clearly demonstrate that mPPAR alpha is the major isoform required for mediating the pleiotropic response resulting from the ac tions of peroxisome proliferators. mPPAR alpha-deficient animals shoul d prove useful to further investigate the role of this receptor in hep atocarcinogenesis, fatty acid metabolism, and cell cycle regulation.