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

Peroxisome proliferators, which function as peroxisome proliferator-activated receptor α (PPARα) agonists, induce peroxisomal, microsomal, and mitochondrial fatty acid oxidation enzymes, in conjunction with peroxisome proliferation, in liver cells. Sustained activation of PPARα leads to the development of liver tumors in rats and mice. The assertion that synthetic PPARα 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 PPARα ligands, we determined the functional competency of human PPARα in vivo and compared its potency with that of mouse PPARα. Recombinant adenovirus that expresses human or mouse PPARα was produced and administered intravenously to PPARα-deficient mice. Human as well as mouse PPARα 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 PPARα is functionally competent and is equally as dose-sensitive as mouse PPARα in inducing peroxisome proliferation within the context of mouse liver environment and that it can heterodimerize with mouse retinoid X receptor, and this human PPARα-mouse retinoid X receptor chimeric heterodimer transcriptionally activates mouse PPARα target genes in a manner qualitatively similar to that of mouse PPARα.