Shared regulation of UGT1A7 by hepatocyte nuclear factor (HNF) 1alpha and HNF4alpha.
Substrates for glucuronidation include endogenous and xenobiotic compounds such as environmental carcinogens and drugs, as well as the chemotherapeutic agent irinotecan. The UDP-glucuronosyltransferase (UGT) 1A7 gene is expressed in the upper gastrointestinal tract and the lung but is not expressed in the liver. The transcriptional regulation of UGT1A7 and the putative influence of single nucleotide polymorphisms (SNPs) are incompletely characterized. UGT1A8, UGT1A9, and UGT1A10, which are highly homologous to UGT1A7, have been reported to be transcriptionally regulated by hepatocyte nuclear factors (HNFs). In this study, we show the activation of UGT1A7 by the aforementioned transcription factors. Sequence analyses, mutagenesis, reporter gene experiments, small interfering RNA silencing, chromatin immunoprecipitation, and electromobility shift assays identified five HNF binding sites in the proximal promoter region of UGT1A7 that were regulated by HNF1alpha and HNF4alpha. Activation by HNF1alpha was lower in the presence of the UGT1A7 -57G SNP. In contrast to liver-expressed UGT1A9, transcriptional activation of UGT1A7 by HNF4alpha was lower and dependent on higher HNF4alpha concentrations, which may contribute to the observed differences in tissue expression patterns. Therefore, a specific role of HNF in the transcriptional control of UGT1A7 is shown and characterized, which may contribute to its tissue specificity and function.
Ehmer
Ursula
U
Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, 30625 Hannover, Germany.
Kalthoff
Sandra
S
Lankisch
Tim O
TO
Freiberg
Nicole
N
Manns
Michael P
MP
Strassburg
Christian P
CP
D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002478:Cells, Cultured; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics*; D014453:Glucuronosyltransferase / Q000096:biosynthesis* / Q000235:genetics*; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000502:physiology*; D051557:Hepatocyte Nuclear Factor 4 / Q000502:physiology*; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D015533:Transcriptional Activation
D051538:Hepatocyte Nuclear Factor 1-alpha; D051557:Hepatocyte Nuclear Factor 4; D014453:Glucuronosyltransferase; C524630:UGT1A7 protein, human