Targeted Disruption of the α Isoform of the Peroxisome Proliferator-Activated Receptor Gene in Mice Results in Abolishment of the Pleiotropic Effects of Peroxisome Proliferators

TLDR

The study disrupted the ligand‑binding domain of mouse PPARα to create mPPARα‑deficient mice, aiming to elucidate PPAR isoform functions and to use these animals for future research on hepatocarcinogenesis, fatty acid metabolism, and cell cycle regulation. The authors generated mPPARα‑deficient mice via homologous recombination targeting the ligand‑binding domain. mPPARα‑deficient mice are viable, fertile, and show no gross defects, yet they fail to exhibit the classic peroxisome proliferator–induced responses—hepatomegaly, peroxisome proliferation, and target gene activation—demonstrating that mPPARα mediates the pleiotropic effects of peroxisome proliferators.

Abstract

To gain insight into the function of peroxisome proliferator-activated receptor (PPAR) isoforms in rodents, we disrupted the ligand-binding domain of the alpha isoform of mouse PPAR (mPPAR alpha) by homologous recombination. 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 the peroxisome proliferator pleiotropic response when challenged with the classical peroxisome proliferators, clofibrate and Wy-14,643. Following exposure to these chemicals, hepatomegaly, peroxisome proliferation, and transcriptional-activation of target genes were not observed. These results clearly demonstrate that mPPAR alpha is the major isoform required for mediating the pleiotropic response resulting from the actions of peroxisome proliferators. mPPAR alpha-deficient animals should prove useful to further investigate the role of this receptor in hepatocarcinogenesis, fatty acid metabolism, and cell cycle regulation.