Evidence for peroxisome proliferator-activated receptor (PPAR)alpha-independent peroxisome proliferation: effects of PPARgamma/delta-specific agonists in PPARalpha-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. 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.
DeLuca
J G
JG
Department of Safety Assessment/Genetic and Cellular Toxicology, Merck Research Laboratories, West Point, Pennsylvania 19438, USA. delucaj@merck.com
Doebber
T W
TW
Kelly
L J
LJ
Kemp
R K
RK
Molon-Noblot
S
S
Sahoo
S P
SP
Ventre
J
J
Wu
M S
MS
Peters
J M
JM
Gonzalez
F J
FJ
Moller
D E
DE
D000818:Animals; D005260:Female; D005786:Gene Expression Regulation; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009929:Organ Size / Q000187:drug effects; D020025:Peroxisome Proliferators / Q000494:pharmacology*; D020675:Peroxisomes / Q000187:drug effects* / Q000502:physiology; D011743:Pyrimidines / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D020025:Peroxisome Proliferators; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; C006253:pirinixic acid; C089946:2,4-thiazolidinedione