Influence of peroxisome proliferator-activated receptor alpha on ubiquinone biosynthesis.
The control of ubiquinone biosynthesis by peroxisome proliferators was investigated using peroxisome proliferator activated receptor alpha (PPARalpha)-null mice. Administration of 2-(diethylhexyl)phthalate to control mice resulted in elevated ubiquinone levels in the liver, while dolichol, dolichyl-P and cholesterol concentrations remained unchanged. In PPARalpha-null mice, the level of these lipids were similar to control levels and administration of the peroxisome proliferator did not increase the levels of ubiquinone. The increase in ubiquinone levels was the result of increased synthesis. Induction was most pronounced in liver, kidney and heart, which have relatively high levels of PPARalpha. When the tissue concentration of hydrogen peroxide was elevated by inhibition of catalase activity with aminotriazole, the amount of ubiquinone was not increased, suggesting that the induction of ubiquinone synthesis occured through a direct mechanism. The activities of branch-point enzymes FPP-synthase, squalene synthase, cis-prenyltransferase, trans-prenyltransferase and NPHB-transferase were substantially increased in control but not in PPARalpha-null mice after treatment with peroxisome proliferators. These data suggest that the induction of ubiquinone biosynthesis after administration of peroxisome proliferators is dependent on the PPARalpha through regulation of some of the mevalonate pathway enzymes.
Turunen
M
M
Department of Biochemistry, Stockholm University, Stockholm, S-106 91, Sweden. Mikael@biokemi.su.se
Peters
J M
JM
Gonzalez
F J
FJ
Schedin
S
S
Dallner
G
G
D019883:Alkyl and Aryl Transferases / Q000378:metabolism; D000818:Animals; D002374:Catalase / Q000037:antagonists & inhibitors / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D004051:Diethylhexyl Phthalate / Q000494:pharmacology; D004288:Dolichol Phosphates / Q000378:metabolism; D004286:Dolichols / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000378:metabolism; D017353:Gene Deletion; D006207:Half-Life; D006861:Hydrogen Peroxide / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008798:Mevalonic Acid / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009928:Organ Specificity; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D014451:Ubiquinone / Q000096:biosynthesis* / Q000378:metabolism
D004288:Dolichol Phosphates; D004286:Dolichols; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C028306:dolichol monophosphate; D014451:Ubiquinone; D002784:Cholesterol; D006861:Hydrogen Peroxide; D004051:Diethylhexyl Phthalate; D002374:Catalase; D019883:Alkyl and Aryl Transferases; D013186:Farnesyl-Diphosphate Farnesyltransferase; D008798:Mevalonic Acid