title: Coordinate regulation of Cyp2e1 by β-catenin- and hepatocyte nuclear factor 1α-dependent signaling.
abstract: Depending on their position within the liver lobule, hepatocytes fulfill different metabolic functions. Cytochrome P450 (CYP) 2E1 is a drug-metabolizing enzyme which is exclusively expressed in hepatocytes surrounding branches of the hepatic central vein. Previous publications have shown that signaling through the Wnt/β-catenin pathway, a major determinant of liver zonation, and the hepatocyte-enriched transcription factor HNF (hepatocyte nuclear factor) 1α participate in the regulation of the gene. This study was aimed to decipher the molecular mechanisms by which the two transcription factors, β-catenin and HNF1α, jointly regulate CYP2E1 at the gene promoter level. Chromatin immunoprecipitation identified a conserved Wnt/β-catenin-responsive site (WRE) in the murine Cyp2e1 promoter adjacent to a known HNF1α response element (HNF1-RE). In vitro analyses demonstrated that both, activated β-catenin and HNF1α, are needed for the full response of the promoter. The WRE was dispensable for β-catenin-mediated effects on the Cyp2e1 promoter, while activity of β-catenin was integrated into the promoter response via the HNF1-RE. Physical interaction of β-catenin and HNF1α was demonstrated by co-immunoprecipitation. In conclusion, present data the first time identify and characterize the interplay of HNF1α and β-catenin and elucidate molecular determinants of CYP2E1 expression in the liver.
authors.affiliation: Natural and Medical Sciences Institute at the University of Tübingen, Markwiesenstr. 55, 72770 Reutlingen, Germany.
authors.forename: Nicola
authors.initials: N
authors.lastname: Groll
authors.affiliation: University of Tübingen, Dept. of Toxicology, Wilhelmstr. 56, 72074 Tübingen, Germany.
authors.forename: Tamara
authors.initials: T
authors.lastname: Petrikat
authors.affiliation: University of Tübingen, Dept. of Toxicology, Wilhelmstr. 56, 72074 Tübingen, Germany.
authors.forename: Silvia
authors.initials: S
authors.lastname: Vetter
authors.affiliation: Institut Cochin, INSERM U1016, CNRS, UMR8104, Equipe labellisée Ligue Nationale Contre le Cancer, Université Paris Descartes, 24 rue du Faubourg Saint-Jacques, 75014 Paris, France.
authors.forename: Sabine
authors.initials: S
authors.lastname: Colnot
authors.affiliation: Natural and Medical Sciences Institute at the University of Tübingen, Markwiesenstr. 55, 72770 Reutlingen, Germany.
authors.forename: Frederik
authors.initials: F
authors.lastname: Weiss
authors.affiliation: Natural and Medical Sciences Institute at the University of Tübingen, Markwiesenstr. 55, 72770 Reutlingen, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Poetz
authors.affiliation: Natural and Medical Sciences Institute at the University of Tübingen, Markwiesenstr. 55, 72770 Reutlingen, Germany.
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Joos
authors.affiliation: Natural and Medical Sciences Institute at the University of Tübingen, Markwiesenstr. 55, 72770 Reutlingen, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Rothbauer
authors.affiliation: University of Tübingen, Dept. of Toxicology, Wilhelmstr. 56, 72074 Tübingen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Schwarz
authors.affiliation: University of Tübingen, Dept. of Toxicology, Wilhelmstr. 56, 72074 Tübingen, Germany; Federal Institute for Risk Assessment, Dept. Food Safety, Max-Dohrn-Str. 8-10, 10589 Berlin, Germany. Electronic address: Albert.Braeuning@bfr.bund.de.
authors.forename: Albert
authors.initials: A
authors.lastname: Braeuning
mesh_terms: D000818:Animals; D047369:Chromatin Immunoprecipitation; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D005786:Gene Expression Regulation; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D051538:Hepatocyte Nuclear Factor 1-alpha; D051176:beta Catenin; D019392:Cytochrome P-450 CYP2E1
keywords: Drug metabolism; Gene expression; Liver zonation; Perivenous; Wnt signaling