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Vol. 58, Issue 3, 470-476, September 2000
-Independent Peroxisome Proliferation: Effects of
PPAR
/
-Specific Agonists in PPAR-Null Mice
Department of Molecular Endocrinology (T.W.D., L.J.K., S.P.S.,
J.V., M.S.W., D.E.M.), Merck Research Laboratories, Rahway, New Jersey;
Department of Safety Assessment/Genetic and Cellular Toxicology
(J.G.D., R.K.K., S.M.-N.), Merck Research Laboratories, West Point,
Pennsylvania; and Laboratory of Metabolism (J.M.P., F.J.G.), National
Cancer Institute, National Institutes of Health, Bethesda,
Maryland
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)
, 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
is predominantly expressed in
adipocytes where it mediates differentiation; PPAR
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 agonists or dual PPAR/PPAR agonists, lacking
apparent murine PPAR agonist activity, cause
peroxisome proliferation in CD-1 mice. We therefore made use of PPAR
knockout mice to investigate whether these effects resulted from
agonism of PPAR by these agents at very high dose levels or whether
PPAR (or PPAR) 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-independent effects.
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