Coordinate regulation of Cyp2e1 by β-catenin- and hepatocyte nuclear factor 1α-dependent signaling

被引:15
|
作者
Groll, Nicola [1 ]
Petrikat, Tamara [2 ]
Vetter, Silvia [2 ]
Colnot, Sabine [3 ]
Weiss, Frederik [1 ]
Poetz, Oliver [1 ]
Joos, Thomas O. [1 ]
Rothbauer, Ulrich [1 ]
Schwarz, Michael [2 ]
Braeuning, Albert [2 ,4 ]
机构
[1] Univ Tubingen, Nat & Med Sci Inst, Markwiesenstr 55, D-72770 Reutlingen, Germany
[2] Univ Tubingen, Dept Toxicol, Wilhelmstr 56, D-72074 Tubingen, Germany
[3] Univ Paris 05, Inst Cochin, Equipe Labellisee Ligue Natl Canc, INSERM U1016,CNRS,UMR8104, 24 Rue Faubourg St Jacques, F-75014 Paris, France
[4] Fed Inst Risk Assessment, Dept Food Safety, Max Dohrn Str 8-10, D-10589 Berlin, Germany
关键词
Liver zonation; Wnt signaling; Drug metabolism; Perivenous; Gene expression; ARYL-HYDROCARBON RECEPTOR; CONSTITUTIVE ANDROSTANE RECEPTOR; MOUSE-LIVER; WNT/BETA-CATENIN; POSTTRANSCRIPTIONAL REGULATION; CYTOCHROME-P450; EXPRESSION; DIABETES-MELLITUS; GENE-EXPRESSION; MURINE LIVER; HA-RAS;
D O I
10.1016/j.tox.2016.05.004
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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/beta-catenin pathway, a major determinant of liver zonation, and the hepatocyte-enriched transcription factor HNF (hepatocyte nuclear factor) 1 alpha participate in the regulation of the gene. This study was aimed to decipher the molecular mechanisms by which the two transcription factors, beta-catenin and HNF1 alpha, jointly regulate CYP2E1 at the gene promoter level. Chromatin immunoprecipitation identified a conserved Wnt/beta-catenin-responsive site (WRE) in the murine Cyp2e1 promoter adjacent to a known HNF1 alpha response element (HNF1-RE). In vitro analyses demonstrated that both, activated beta-catenin and HNF1 alpha, are needed for the full response of the promoter. The WRE was dispensable for beta-catenin-mediated effects on the Cyp2e1 promoter, while activity of beta-catenin was integrated into the promoter response via the HNF1-RE. Physical interaction of beta-catenin and HNF1 alpha was demonstrated by co-immunoprecipitation. In conclusion, present data the first time identify and characterize the interplay of HNF1 alpha and beta-catenin and elucidate molecular determinants of CYP2E1 expression in the liver. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
引用
收藏
页码:40 / 48
页数:9
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