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J. Biol. Chem., Vol. 278, Issue 35, 32852-32860, August 29, 2003

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Peroxisome Proliferator-activated Receptor Induces Hepatic Expression of the Human Bile Acid Glucuronidating UDP-glucuronosyltransferase 2B4 Enzyme^*

Olivier Barbier , Daniel Duran-Sandoval , Inés Pineda-Torra , Vladimir Kosykh , Jean-Charles Fruchart  and Bart Staels  ¶

From the Unité de Recherche 545, Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'Athérosclérose, Institut Pasteur de Lille and the Faculté de Pharmacie, Université de Lille II, 59019 Lille, France and Institute of Experimental Cardiology, Russian Cardiology Complex, Moscow 121552, Russia

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 (PPAR), which mediates the hypolipidemic action of fibrates. Incubation of human hepatocytes or hepatoblastoma HepG2 and Huh7 cells with synthetic PPAR 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 wild type and null mice revealed that PPAR 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 agonists may control the catabolism of cytotoxic bile acids and reinforce recent data indicating that PPAR, 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.

Received for publication, May 22, 2003

^* This work was supported by grants from the Fondation Lefoulon-Delalande, Institut de France (to O. B.), the European community (ERBFMBICT983214) (to I. P.-T.), the ministerio de Hacienda del Gobierno de Chile (to D. D.-S.), the Fonds Européens de Développement Régional, Conseil Régional Région Nord/Pas-de-Calais (Genopole Project Grant 01360124), and the Leducq Foundation (to B. S. and J.-C. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Unité INSERM 545, Institut Pasteur de Lille, 1, rue du Pr Calmette, BP 245, 59019 Lille, France. Tel.: 33-3-20-87-73-87; Fax: 33-3-20-87-71-98; E-mail: bart.staels{at}pasteur-lille.fr.

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