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Originally published In Press as doi:10.1074/jbc.M300749200 on February 11, 2003

J. Biol. Chem., Vol. 278, Issue 16, 13975-13983, April 18, 2003
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The UDP-glucuronosyltransferase 1A9 Enzyme Is a Peroxisome Proliferator-activated Receptor alpha  and gamma  Target Gene*

Olivier BarbierDagger , Lyne Villeneuve§, Virginie BocherDagger , Coralie FontaineDagger , Ines Pineda TorraDagger , Christian DuhemDagger , Vladimir Kosykh, Jean-Charles FruchartDagger , Chantal Guillemette§, and Bart StaelsDagger ||

From the Dagger  UR 545 INSERM, Département d'Athérosclérose, Institut Pasteur de Lille and the Faculté de Pharmacie, Université de Lille II, Lille 59019, France, the § Oncology and Molecular Endocrinology Research Center, CHUL Research Center and Faculty of Pharmacy, Laval University, Quebec G1V 4G2, Canada, and  Institute of Experimental Cardiology, Russian Cardiology Complex, Moscow 121552, Russia

Peroxisome proliferator-activated receptor (PPAR) alpha  and gamma  are ligand-activated transcription factors belonging to the nuclear receptor family. PPARalpha mediates the hypolipidemic action of the fibrates, whereas PPARgamma is a receptor for the antidiabetic glitazones. In the present study, the UDP-glucuronosyltransferase (UGT) 1A9 enzyme is identified as a PPARalpha and PPARgamma target gene. UGTs catalyze the glucuronidation reaction, which is a major pathway in the catabolism and elimination of numerous endo- and xenobiotics. Among the UGT1A family enzymes, UGT1A9 metabolizes endogenous compounds, including catecholestrogens, and xenobiotics, such as fibrates and to a lesser extent troglitazone. Treatment of human hepatocytes and macrophages and murine adipocytes with activators of PPARalpha or PPARgamma resulted in an enhanced UGT1A9 expression and activity. In addition, disruption of the PPARalpha gene in mice completely abolished the PPARalpha agonist-induced UGT1A9 mRNA and activity levels. A PPAR response element was identified in the promoter of UGT1A9 at positions -719 to -706 bp by transient transfection and electromobility shift assays. Considering the role of UGT1A9 in catecholestrogen metabolism, PPARalpha and PPARgamma activation may contribute to the protection against genotoxic catecholestrogens by stimulating their inactivation in glucuronide derivatives. Furthermore, since UGT1A9 is involved in the catabolism of fibrates, these results suggest that PPARalpha and PPARgamma may control the intracellular level of active fibrates.

* This work was supported by grants from the Fondation Lefoulon-Delalande, Institut de France (to O. B.), European Community Grant ERBFMBICT983214 (to I. P. T.), Fonds Européens de Developpement Régional, Conseil Régional Région Nord/Pas-de-Calais Genopole Project 01360124, grants from the Leducq Foundation (to B. S. and J. C. F.), Canadian Institutes of Health Research Grants MOP-44032 and MSH-46809, and Fonds de la Recherche en Santé du Québec Grant 13408-166 (to C. G.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

|| To whom all 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@pasteur-lille.fr.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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