The impact of beta-catenin and Ras signaling on zonal gene expression was analyzed in vivo by use of different transgenic mouse strains. Zone-specific physiological activation and antagonism of the two pathways were demonstrated. Transcriptome profiles of Ctnnb1- and Ha-ras-mutated tumors closely resembled those of perivenous and periportal hepatocytes. In vitro experiments with primary hepatocytes and hepatoma cells confirmed the role of beta-catenin signaling in the induction of ‘perivenous’ gene expression, particularly of drug-metabolizing enzymes. Inducibility of drug-metabolizing enzymes by xenobiotics was demonstrated to be modulated by beta-catenin in vitro and in vivo. beta-catenin thereby activated transcription by both direct beta-catenin/ TCF-dependent and indirect mechanisms.
Serum components were shown to inhibit beta-catenin-mediated transcription and to induce the expression of ‘periportal’ markers. Serum-mediated inhibition of betacatenin signaling was not exclusively linked to Ras activation, but also to the action of different ligand-activated nuclear receptors, thus suggesting a complex interplay of different blood-borne molecules in the periportal repression of betacatenin signaling.
In summary, the results favor the hypothesis that gene expression patterns in periportal and perivenous hepatocytes are regulated, at least in part, by Ras- and betacatenin-dependent signaling pathways. In the perivenous areas of the liver lobule, betacatenin seems to act as a master regulator of both basal and inducible expression of enzymes involved in the metabolism of drugs and xenobiotics.