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Activating and Inhibitory Functions of WNT/β-catenin in the Induction of Cytochromes P450 by Nuclear Receptors in HepaRG Cells

Abstract:

The WNT/β-catenin signaling pathway has been identified as an important endogenous regulator of hepatic cytochrome P450 (CYP) expression in mouse liver. In particular, it is involved in the regulation of CYP expression in response to exposure to xenobiotic agonists of the nuclear receptors CAR, AhR, and Nrf2. In order to systematically elucidate the impact of the WNT/β-catenin pathway on the regulation and inducibility of major human cytochrome P450 enzymes, HepaRG cells were treated with either the WNT/β-catenin signaling pathway agonist, WNT3a, or with siRNA directed against β-catenin, alone or in combination with a panel of activating ligands for AhR (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD), CAR (6-(4-Chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl)oxime, CITCO), PXR (rifampicin) and PPARα (4-Chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid, WY14,643). Assessment of CYP gene expression and enzymatic activity following downregulation or activation of the WNT/β-catenin pathway revealed a requirement of β-catenin in the AhR-, CAR- and PXR-mediated induction of CYP1A, CYP2B6 and CYP3A4 (for CAR and PXR) and additionally of CYP2C8 (for PXR) gene expression. In contrast, activation of the WNT/β-catenin pathway prevented PPARα-mediated induction of CYP1A, CYP2C8 and CYP3A4 genes, suggesting a dominant-negative role of β-catenin in PPARα-mediated regulation of these genes. Our data indicate a significant impact of the WNT/β-catenin pathway on the regulation of cytochromes P450 enzymes in human hepatocytes and reveal a novel crosstalk between β-catenin and PPARα signaling pathways in the regulation of CYP expression.

25824487

Projects: A3.4: Linking signalling to metabolic functions, B5: Cell-cell communication influences detoxifying functions in hepatocytes, Showcase Steatosis

Mol. Pharmacol.
Mol. Pharmacol. :
1st Apr 2015

Maria Thomas, Christine Bayha, Silvia Vetter, Ute Hofmann, Michael Schwarz, Ulrich M Zanger, Albert Braeuning

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[Maria Thomas] [Ute Hofmann] [Ulrich Zanger]

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Views: 1795
  • Created: 7th Apr 2015 at 14:00

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