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Hepatic Expression of the UGT1A9 Gene Is Governed by Hepatocyte Nuclear Factor 4

UR 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, Lille, France (O.B., H.D., J.C.F., B.S.); Canada Research Chair in Pharmacogenomics, Oncology and Molecular Endocrinology Research Center, CHUL Research Center and Faculty of Pharmacy, Laval University, Quebec, Canada (H.G., L.V. C.G.); and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (Y.I., A.K., F.G.)

UDP-glucuronosyltransferase (UGT) enzymes catalyze the glucuronidation reaction, which is a major pathway in the catabolism and elimination of numerous endo- and xenobiotics. Among the UGT enzyme family members, the UGT1A7, UGT1A8, UGT1A9, and UGT1A10 isoforms are issued from a single gene through differential splicing. However, these enzymes display distinct tissue-specific expression patterns. Indeed, UGT1A7, UGT1A8, and UGT1A10 are exclusively expressed in extrahepatic tissues, whereas UGT1A9 transcripts are found at high concentrations in liver. In the present study, we report that the liver-enriched hepatocyte nuclear factor 4 (HNF4)- controls the hepatic expression of the UGT1A9 enzyme. Liver-specific disruption of the HNF4 gene in mice drastically decreases liver UGT1A9 mRNA levels. Furthermore, an HNF4 response element (HNF4 RE) was identified in the promoter of human UGT1A9 at position -372 to -360 base pairs by transient transfection, electrophoretic mobility shift assays, and chromatin immunoprecipitation experiments. It is interesting that this response element is absent in the proximal UGT1A7, UGT1A8, and UGT1A10 gene promoters. In conclusion, the present study identifies HNF4 as a major factor for the control of UGT1A9 hepatic expression and suggests that the absence of UGT1A7, UGT1A8, and UGT1A10 expression in the liver is caused by, at least in part, a few base pair changes in their promoter sequences in the region corresponding to the HNF4 RE of the UGT1A9 gene.

Address correspondence to: Dr. Bart Staels, Unité INSERM 545, Institut Pasteur de Lille, 1, rue du Pr Calmette, BP 245, 59019 Lille, France. E-mail: bart.staels{at}pasteur-lille.fr

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