Evidence for Peroxisome Proliferator-Activated Receptor (PPAR)α-Independent Peroxisome Proliferation: Effects of PPARγ/δ-Specific Agonists in PPARα-Null Mice

Abstract

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. PPARgamma is predominantly expressed in adipocytes where it mediates differentiation; PPARdelta is a widely expressed orphan receptor with yet unresolved physiologic functions. In the course of characterizing newer PPAR ligands, we noted that highly selective PPARgamma agonists or dual PPARgamma/PPARdelta agonists, lacking apparent murine PPARalpha agonist activity, cause peroxisome proliferation in CD-1 mice. We therefore made use of PPARalpha knockout mice to investigate whether these effects resulted from agonism of PPARalpha by these agents at very high dose levels or whether PPARgamma (or PPARdelta) 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 PPARalpha-independent effects.

Liver-specific disruption of PPARγ in leptin-deficient mice improves fatty liver but aggravates diabetic phenotypes

“…However, this raises questions about why PPARγ can specially regulate the expression of these genes when PPARα is predominantly expressed in liver of ob/ob-PPARγ(fl/fl)AlbCre + and ob/ob-PPARγ(fl/fl)AlbCre -mice. Treatment of wildtype and PPARα-null mice with the highly selective PPARγ agonist rosiglitazone induces acyl-CoA oxidase, fatty acid-binding protein, and CYP4A mRNA's, all known PPARα target genes (41). These results indicate that although expression of PPARγ in liver is lower than PPARα, it appears that residual PPARγ is capable of mimicking PPARα function with activation by potent agonist.…”

Gene Profiling in the Livers of Wild-type and PPARα-Null Mice Exposed to Perfluorooctanoic Acid

“…598 ROSEN ET AL. TOXICOLOGIC PATHOLOGY functional overlap may exist between the various PPAR isoforms (DeLuca et al, 2000). More recently, peroxisome proliferation was reported in PPARα-null mice treated with fenofibrate, a drug thought to function primarily through transactivation of PPARα, further suggesting that a non-PPARα mechanism exists for peroxisome regulation in the murine liver (Zhang et al, 2006).…”

Transcriptional Regulation of Metabolism

“…Such a treatment results in a dose-dependent activation of fatty acid ␤-oxidation in the quadriceps muscles, sustained by the higher expression of genes encoding enzymes involved in mitochondrial fatty acid catabolism, such as fatty acid transport proteins (FAT and LCAD) as well as UCP2 and UCP3 (294). Overlapping activities of PPAR␤ with PPAR␣ with respect to fatty acid oxidation are also described in the heart, where a mutation of PPAR␣ is partially compensated by PPAR␤ (36,50). In this organ, PPAR␤ may have a dominant role, as a cardiac specific disruption of PPAR␤ results in a cardiomyopathy that develops as early as at 4 mo of age and is associated with a general decrease in the cardiac expression of all genes involved in ␤-oxidation (35).…”