b-catenin signaling can be both a physiological and oncogenic pathway in the liver. It controls compartmentalized gene expression, allowing the liver to ensure its essential metabolic function. It is activated by mutations in 20%-40% of hepatocellular carcinomas (HCCs) with specific metabolic features. We decipher the molecular determinants of b-catenindependent zonal transcription using mice with b-catenin-activated or -inactivated hepatocytes, characterizing in vivo their chromatin occupancy by T-cell factor (Tcf )24 and b-catenin, transcriptome, and metabolome. We find that Tcf-4 DNA bindings depend on bcatenin. Tcf-4/b-catenin binds Wnt-responsive elements preferentially around b-catenininduced genes. In contrast, genes repressed by b-catenin bind Tcf-4 on hepatocyte nuclear factor 4 (Hnf-4)-responsive elements. b-Catenin, Tcf-4, and Hnf-4a interact, dictating bcatenin transcription, which is antagonistic to that elicited by Hnf-4a. Finally, we find the drug/bile metabolism pathway to be the one most heavily targeted by b-catenin, partly through xenobiotic nuclear receptors. Conclusions: b-catenin patterns the zonal liver together with Tcf-4, Hnf-4a, and xenobiotic nuclear receptors. This network represses lipid metabolism and exacerbates glutamine, drug, and bile metabolism, mirroring HCCs with b-catenin mutational activation. (HEPATOLOGY 2014;59:2344-2357 See Editorial on Page 2080 T he adult liver is a quiescent organ, fully compartmentalized to accomplish its crucial metabolic role. Its vasculature gives rise to two distinct hepatocyte populations: one located in the vicinity of the portal vein and the other around the central vein. 1 Pericentral (PC) hepatocyte metabolism is complementary to that of periportal (PP) hepatocytes in terms of energy, ammonia, and xenobiotic metabolism. This complementarity arises as a result of the production of distinct specialized proteins in the two zones. 1,2 It has been demonstrated that the Wnt/b-catenin pathway is the master transcriptional regulator of this zonal metabolism, and that control is rendered by a Wnt morphogenetic concentration gradient high in PC hepatocytes and decreasing toward PP hepatocytes. 3,4

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