RT Journal Article SR Electronic T1 Hepatic Expression of the UGT1A9 Gene Is Governed by Hepatocyte Nuclear Factor 4α JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 241 OP 249 DO 10.1124/mol.104.003863 VO 67 IS 1 A1 Olivier Barbier A1 Hugo Girard A1 Yusuke Inoue A1 Hélène Duez A1 Lyne Villeneuve A1 Akihide Kamiya A1 Jean-Charles Fruchart A1 Chantal Guillemette A1 Frank J. Gonzalez A1 Bart Staels YR 2005 UL http://molpharm.aspetjournals.org/content/67/1/241.abstract AB 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)-α controls the hepatic expression of the UGT1A9 enzyme. Liver-specific disruption of the HNF4α gene in mice drastically decreases liver UGT1A9 mRNA levels. Furthermore, an HNF4α response element (HNF4α 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 HNF4α 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 HNF4α RE of the UGT1A9 gene.