Hepatic Expression of the UGT1A9 Gene Is Governed by Hepatocyte Nuclear Factor 4α
- 6 October 2004
- journal article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in Molecular Pharmacology
- Vol. 67 (1), 241-249
- https://doi.org/10.1124/mol.104.003863
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)-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.Keywords
This publication has 40 references indexed in Scilit:
- Cloning and Characterization of the Human UDP-glucuronosyltransferase 1A8, 1A9, and 1A10 Gene PromotersPublished by Elsevier BV ,2003
- Role of the hepatocyte nuclear factor 4α in control of the pregnane X receptor during fetal liver developmentHepatology, 2003
- The UDP-glucuronosyltransferase 1A9 Enzyme Is a Peroxisome Proliferator-activated Receptor α and γ Target GenePublished by Elsevier BV ,2003
- Hepatocyte nuclear factor 1α: A key mediator of the effect of bile acids on gene expressionHepatology, 2003
- Cell Clones Selected from the Huh7 Human Hepatoma Cell Line Support Efficient Replication of a Subgenomic GB Virus B RepliconJournal of Virology, 2002
- Activation of the Insulin Gene Promoter through a Direct Effect of Hepatocyte Nuclear Factor 4αJournal of Biological Chemistry, 2002
- Characterization of the Human PPAR Promoter: Identification of a Functional Nuclear Receptor Response ElementMolecular Endocrinology, 2002
- UDP Glucuronosyltransferase mRNA Levels in Human Liver DiseaseDrug Metabolism and Disposition, 2002
- The Monkey and Human Uridine Diphosphate-Glucuronosyltransferase UGT1A9, Expressed in Steroid Target Tissues, Are Estrogen-Conjugating EnzymesEndocrinology, 1999
- Characterization of Two UDP Glucuronosyltransferases That Are Predominantly Expressed in Human ColonBiochemical and Biophysical Research Communications, 1998