Human Peroxisome Proliferator-activated Receptor (PPAR ) Supports the Induction of Peroxisome Proliferation in PPAR -deficient Mouse Liver*

Peroxisome proliferators, which function as peroxisome proliferator-activated receptor (PPAR ) agonists, induce peroxisomal, microsomal, and mitochondrial fatty acid oxidation enzymes, in conjunction with peroxisome proliferation, in liver cells. Sustained activation of PPAR leads to the development of liver tumors in rats and mice. The assertion that synthetic PPAR ligands pose negligible carcinogenic risk to humans is attributable, in part, to the failure to observe peroxisome proliferation in human hepatocytes. To explore the mechanism(s) of species-specific differences in response to PPAR ligands, we determined the functional competency of human PPAR in vivo and compared its potency with that of mouse PPAR . Recombinant adenovirus that expresses human or mouse PPAR was produced and administered intravenously to PPAR -deficient mice. Human as well as mouse PPAR fully restored the development of peroxisome proliferator-induced immediate pleiotropic responses, including peroxisome proliferation and enhanced expression of genes involved in lipid metabolism as well as nonperoxisomal genes, such as CD36, Ly-6D, Rbp7, monoglyceride lipase, pyruvate dehydrogenase kinase-4, and C3f, that have been identified recently to be up-regulated in livers with peroxisome proliferation. These studies establish that human PPAR is functionally competent and is equally as dose-sensitive as mouse PPAR in inducing peroxisome proliferation within the context of mouse liver environment and that it can heterodimerize with mouse retinoid X receptor, and this human PPAR mouse retinoid X receptor chimeric heterodimer transcriptionally activates mouse PPAR target genes in a manner qualitatively similar to that of mouse PPAR .