Received for publication June 14, 2004.
Revised September 28, 2004.
Accepted for publication September 28, 2004.

Hepatic expression of the UGT1A9 gene is governed by HNF4

Abstract

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, a HNF4 response element (HNF4 RE) was identified in the promoter of human UGT1A9 at position -372 to -360 bp by transient transfection, electrophoretic mobility shift assays and chromatin immunoprecipitation experiments. Interestingly, 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 due, at least in part, to few base pair changes in their promoter sequences in the region corresponding to the HNF4 RE of the UGT1A9 gene.

Key words: DNA binding sites, Promoter analysis, Receptor binding studies, Regulation of gene expression, Phase II enzymes, Regulation - transcriptional, UDP-glucuronyltransferases