Hepatic expression of the UGT1A9 gene is governed by hepatocyte nuclear factor 4alpha.
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)-alpha controls the hepatic expression of the UGT1A9 enzyme. Liver-specific disruption of the HNF4alpha gene in mice drastically decreases liver UGT1A9 mRNA levels. Furthermore, an HNF4alpha response element (HNF4alpha 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 HNF4alpha 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 HNF4alpha RE of the UGT1A9 gene.
Unité INSERM 545, Institut Pasteur de Lille, 1 rue du Pr Calmette, BP 245, 59019 Lille, France.
Olivier
O
Barbier
Hugo
H
Girard
Yusuke
Y
Inoue
Hélène
H
Duez
Lyne
L
Villeneuve
Akihide
A
Kamiya
Jean-Charles
JC
Fruchart
Chantal
C
Guillemette
Frank J
FJ
Gonzalez
Bart
B
Staels
D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D014453:Glucuronosyltransferase / Q000235:genetics*; D051557:Hepatocyte Nuclear Factor 4; D006801:Humans; D008099:Liver / Q000201:enzymology*; D016297:Mutagenesis, Site-Directed; D010750:Phosphoproteins / Q000502:physiology*; D010957:Plasmids; D011401:Promoter Regions, Genetic; D011994:Recombinant Proteins / Q000378:metabolism; D015183:Restriction Mapping; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000502:physiology*; D000090264:UDP-Glucuronosyltransferase 1A9
D004268:DNA-Binding Proteins; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D010750:Phosphoproteins; D011994:Recombinant Proteins; D014157:Transcription Factors; C000715591:UGT1A9 protein, human; C000715592:Ugt1a9 protein, mouse; D014453:Glucuronosyltransferase; D000090264:UDP-Glucuronosyltransferase 1A9