Gender-specific interplay of signaling through β-catenin and car in the regulation of xenobiotic-induced hepatocyte proliferation

The connection of β-catenin and phenobarbital in murine hepatocarcinogenesis: a critical discussion of Awuah et al., PLoS ONE 7(6):e39771, 2012

“…Similar observations were made with the PB-like tumor promoter PCB153 (Strathmann et al 2006). Furthermore, CAR and b-catenin interact in the regulation of enzyme induction and hepatocyte proliferation triggered by PB (Braeuning et al 2009;Braeuning et al 2011).…”

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

“…Synergistic activation of target gene expression by b-catenin and the nuclear receptors AhR and CAR has been previously studied in mice as well as in murine cell lines (Braeuning et al, 2009(Braeuning et al, , 2011aGanzenberg et al, 2013;Vaas et al, 2014). Data presented in this article show, for the first time, synergistic effects of the WNT/b-catenin pathway and the receptors AhR, CAR, and PXR in human liver cells.…”

“…The WNT/b-catenin signaling pathway, traditionally well known as a regulator of embryonic development, tissue homeostasis, and carcinogenesis, was recently identified as an important endogenous regulator of hepatic drug metabolism in mouse liver, where the activity of this particular pathway determines hepatic zonation of cytochrome P450 (P450) expression (Loeppen et al, 2005;Hailfinger et al, 2006;Sekine et al, 2006;Braeuning and Schwarz, 2010;Braeuning et al, 2011a;Schreiber et al, 2011) and is also critically involved in the regulation of P450 transcription in response to exposure to xenobiotic agonists of a number of nuclear receptors (Braeuning et al, 2009;Ganzenberg et al, 2013;Vaas et al, 2014). Lipid-and xenobiotic-sensing nuclear receptors pregnane X receptor (PXR, NR1I2), constitutive androstane receptor (CAR, NR1I3), and aryl hydrocarbon receptor (AhR), together with the liverenriched transcription factor peroxisome proliferator-activated receptor (PPAR) a (NR1C1) form networks of transcription factors that coordinately regulate hepatic expression of the majority of drug-metabolizing P450s, phase II enzymes, and transporters in response to xenobiotic exposure (Handschin and Meyer, 2005;Pascussi et al, 2008;Pelkonen et al, 2008;Thomas et al, 2013).…”

Interplay of β-Catenin with Xenobiotic-Sensing Receptors and its Role in Glutathione S-Transferase Expression

“…This is supported by the fact that mouse liver adenomas with activated -catenin possess slightly elevated levels of CAR [20,36], whereas livers from mice with hepatocyte-specific knockout of Ctnnb1 exhibit decreased CAR mRNA and protein levels [21,36,88]; see also Table 5. Thus, there is evidence that CAR is a transcriptional target of the Wnt/ -catenin pathway.…”