Influence of peroxisome proliferator-activated receptor alpha on ubiquinone biosynthesis

The control of ubiquinone biosynthesis by peroxisome proliferators was inve stigated using peroxisome proliferator activated receptor alpha (PPAR alpha )-null mice. Administration of 2-(diethylhexyl)phthalate to control mice re sulted in elevated ubiquinone levels in the liver, while dolichol, dolichyl -P and cholesterol concentrations remained unchanged. In PPAR alpha-null mi ce, the level of these Lipids were similar to control levels and administra tion of the peroxisome proliferator did not increase the levels of ubiquino ne. The increase in ubiquinone levels was the result of increased synthesis . Induction was most pronounced in Liver, kidney and heart, which have rela tively high, levels of PPAR alpha. When the tissue concentration of hydroge n peroxide was elevated by inhibition of catalase activity with aminotriazo le, the amount of ubiquinone was not increased, suggesting that the inducti on of ubiquinone synthesis occured through a direct mechanism. The activiti es of branch-point enzymes FPP-synthase, squalene synthase, cis-prenyltrans ferase, trans-prenyltransferase and NPHB-transferase were substantially inc reased in control but not in PPAR alpha-null mice after treatment with pero xisome proliferators. These data suggest that the induction of ubiquinone b iosynthesis after administration of peroxisome proliferators is dependent o n the PPAR alpha through regulation of some of the mevalonate pathway enzym es. (C) 2000 Academic Press.