Peroxisome proliferator-activated receptor alpha induces hepatic expression of the human bile acid glucuronidating UDP-glucuronosyltransferase 2B4 enzyme.
Glucuronidation, a major metabolic pathway for a large variety of endobiotics and xenobiotics, is catalyzed by enzymes belonging to the UDP-glucuronosyltransferase (UGT) family. Among UGT enzymes, UGT2B4 conjugates a large variety of endogenous and exogenous molecules and is considered to be the major bile acid conjugating UGT enzyme in human liver. In the present study, we identify UGT2B4 as a novel target gene of the nuclear receptor peroxisome proliferator-activated receptor alpha (PPAR alpha), which mediates the hypolipidemic action of fibrates. Incubation of human hepatocytes or hepatoblastoma HepG2 and Huh7 cells with synthetic PPAR alpha agonists, fenofibric acid, or Wy 14643 resulted in an increase of UGT2B4 mRNA levels. Furthermore, treatment of HepG2 cells with Wy 14643 induced the glucuronidation of hyodeoxycholic acid, a specific bile acid UGT2B4 substrate. Analysis of UGT2B mRNA and protein levels in PPAR alpha wild type and null mice revealed that PPAR alpha regulates both basal and fibrate-induced expression of these enzymes in rodents also. Finally, a PPAR response element was identified in the UGT2B4 promoter by site-directed mutagenesis and electromobility shift assays. These results demonstrate that PPAR alpha agonists may control the catabolism of cytotoxic bile acids and reinforce recent data indicating that PPAR alpha, which has been largely implicated in the control of lipid and cholesterol metabolism, is also an important modulator of the metabolism of endobiotics and xenobiotics in human hepatocytes.
Barbier
Olivier
O
Unité de Recherche 545, Institut National de la Santé et de la Recherche Médicale, Département d'Athérosclérose, Institut Pasteur de Lille and the Faculté de Pharmacie, Université de Lille II, 59019 Lille, France.
Duran-Sandoval
Daniel
D
Pineda-Torra
Inés
I
Kosykh
Vladimir
V
Fruchart
Jean-Charles
JC
Staels
Bart
B
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D015152:Blotting, Northern; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D014453:Glucuronosyltransferase / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D050356:Lipid Metabolism; D008099:Liver / Q000201:enzymology* / Q000378:metabolism*; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D008954:Models, Biological; D016297:Mutagenesis, Site-Directed; D020025:Peroxisome Proliferators / Q000494:pharmacology; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011743:Pyrimidines / Q000494:pharmacology; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured
D001647:Bile Acids and Salts; D018076:DNA, Complementary; D020025:Peroxisome Proliferators; D011743:Pyrimidines; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D012313:RNA; C006253:pirinixic acid; D002784:Cholesterol; D008156:Luciferases; D014453:Glucuronosyltransferase; C486404:UGT2B4 protein, human