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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The Wnt/beta-catenin pathway is a key developmental pathway for which alterations have been described in various human cancers. The aberrant activation of this pathway is a major event in human hepatocellular carcinoma. Several laboratories have shown that the Wnt/beta-catenin pathway plays an essential role in all phases of liver development and maturation, and is required for the metabolic function of this organ. In this review, we summarize current knowledge regarding the role of the Wnt/beta-catenin pathway in hepatocellular carcinoma pathogenesis and liver biology, and the possibilities for developing new therapeutic interventions based on this knowledge.

Traditional remote sensing applications are often based on pulsed laser illumination with a narrow linewidth and characteristic repetition rate, which are not conducive to covert operation. Whatever methods are employed for covert sensing, a key requirement is for the probe light to be indistinguishable from background illumination. We present a method to perform single-pixel imaging that suppresses the effect of background light and hence improves the signal-to-noise ratio by using correlated photon-pairs produced via spontaneous parametric down conversion. One of the photons in the pair is used to illuminate the object whilst the other acts as a temporal reference, allowing the signal photons to be distinguished from background noise. Understanding the noise regime is key to producing higher contrast images using this heralding method.

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