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 hepati c hypertrophy and hyperplasia, increase peroxisome number, and on chronic h igh-dose administration, lead to rodent liver tumorigenesis. Various lines of evidence have led to the conclusion that these agents induce their pleio tropic effects exclusively via agonism of peroxisome proliferator-activated receptor (PPAR)alpha, a member of the steroid receptor superfamily involve d in the regulation of fatty acid metabolism. Recently, agonists of two oth er members of this receptor family have been identified. PPAR gamma is pred ominantly expressed in adipocytes where it mediates differentiation; PPAR d elta is a widely expressed orphan receptor with yet unresolved physiologic functions. In the course of characterizing newer PPAR ligands, we noted tha t highly selective PPAR gamma agonists or dual PPAR gamma/PPAR delta agonis ts, lacking apparent murine PPAR alpha agonist activity, cause peroxisome p roliferation in CD-1 mice. We therefore made use of PPAR alpha knockout mic e 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 del ta) agonism alone can result in peroxisome proliferation. We report here th at several parameters linked to the hepatic peroxisome proliferation respon se in mice that were seen with these agents resulted from PPAR alpha-indepe ndent effects.