Evidence for peroxisome proliferator-activated receptor (PPAR)alpha-independent peroxisome proliferation: Effects of PPAR gamma/delta-specific agonists in PPAR alpha-Null mice

Peroxisome proliferators are a diverse group of compounds that cause hepatic hypertrophy and hyperplasia, increase peroxisome number, and on chronic high-dose administration, lead to rodent liver tumorigenesis. Various lines of evidence have led to the conclusion that these agents induce their pleiotropic effects exclusively via agonism of peroxisome proliferator-activated receptor (PPAR)alpha, a member of the steroid receptor superfamily involved in the regulation of fatty acid metabolism. Recently, agonists of two other members of this receptor family have been identified. PPAR gamma is predominantly expressed in adipocytes where it mediates differentiation; PPAR delta is a widely expressed orphan receptor with yet unresolved physiologic functions. In the course of characterizing newer PPAR ligands, we noted that highly selective PPAR gamma agonists or dual PPAR gamma/PPAR delta agonists, lacking apparent murine PPAR alpha agonist activity, cause peroxisome proliferation in CD-1 mice. We therefore made use of PPAR alpha knockout mice to investigate whether these effects resulted from agonism of PPAR alpha by these agents at very high dose levels or whether PPAR gamma (or PPAR delta) agonism alone can result in peroxisome proliferation. We report here that several parameters linked to the hepatic peroxisome proliferation response in mice that were seen with these agents resulted from PPAR alpha-independent effects.