Human peroxisome proliferator-activated receptor alpha (PPAR alpha) supports the induction of peroxisome proliferation in PPAR alpha-deficient mouse liver

Peroxisome proliferators, which function as peroxisome proliferator-activat ed receptor alpha (PPAR alpha) agonists, induce peroxisomal, microsomal, an d mitochondrial fatty acid oxidation enzymes, in conjunction with peroxisom e proliferation, in liver cells. Sustained activation of PPAR alpha leads t o the development of liver tumors in rats and mice. The assertion that synt hetic PPAR alpha ligands pose negligible carcinogenic risk to humans is att ributable, in part, to the failure to observe peroxisome proliferation in h uman hepatocytes. To explore the mechanism(s) of species-specific differenc es in response to PPAR alpha ligands, we determined the functional competen cy of human PPAR alpha in vivo and compared its potency with that of mouse PPAR alpha. Recombinant adenovirus that expresses human or mouse PPAR alpha was produced and administered intravenously to PPAR alpha -deficient mice. Human as well as mouse PPAR alpha fully restored the development of peroxi some proliferator-induced immediate pleiotropic responses, including peroxi some proliferation and enhanced expression of genes involved in lipid metab olism as well as nonperoxisomal genes, such as CD36, Ly-6D, Rbp7, monoglyce ride lipase, pyruvate dehydrogenase kinase-4, and CV, that have been identi fied recently to be up-regulated in livers with peroxisome proliferation. T hese studies establish that human PPAR alpha is functionally competent and is equally as dose-sensitive as mouse PPAR alpha in inducing peroxisome pro liferation within the context of mouse liver environment and that it can he terodimerize with mouse retinoid X receptor, and this human PPAR alpha -mou se retinoid X receptor chimeric heterodimer transcriptionally activates mou se PPAR alpha target genes in a manner qualitatively similar to that of mou se PPAR alpha.