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

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• 作者：Nicola Groll^a ; Tamara Petrikat^b ; Silvia Vetter^b ; Sabine Colnot^c ; Frederik Weiss^a ; Oliver Poetz^a ; Thomas O. Joos^a ; Ulrich Rothbauer^a ; Michael Schwarz^b ; Albert Braeuning^b ; ^d ; ^{Albert.Braeuning@bfr.bund.de" class="auth_mail" title="E-mail the corresponding author}
• 关键词：AHR ; aryl hydrocarbon receptor ; ChIP ; chromatin immunoprecipitation ; CMV ; cytomegaly virus ; CYP ; cytochrome P450 ; GS ; glutamine synthetase ; HNF ; hepatocyte nuclear factor ; HNF1-RE ; hepatocyte nuclear factor 1α response element ; IP ; immunoprecipitation ; KO ; knockout ; TCF ; T-cell factor ; WB ; Western blotting ; WRE ; wnt response element
• 刊名：Toxicology
• 出版年：2016
• 出版时间：28 March 2016
• 年：2016
• 卷：350-352
• 期：Complete
• 页码：40-48
• 全文大小：2032 K

文摘

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.