Organ patterning in the adult stage: The role of Wnt/β‐catenin signaling in liver zonation and beyond

Abstract

Wnt/␤-catenin signaling has been found to play key roles in metabolic zonation of adult liver, regeneration, and hepatocellular carcinogenesis. In this review, recent progress in this field is summarized, in particular the rapidly growing knowledge about the various interactions of ␤-catenin with many transcription factors involved in controlling metabolism. These interactions may provide the basis for understanding how the wide range of activities of Wnt/␤-catenin signaling is differentially interpreted. Based on these results, a three-level mode for the molecular interpretation of ␤-catenin activity gradients in liver is proposed favoring cell differentiation, metabolic zonation, and proliferation. While derangement of the combinatorial interplay of the various transcription factors with ␤-catenin at the intermediary activity level may contribute to the development of metabolic diseases, extremely high activation of ␤-catenin may eventually lead to initiation and progression of hepatocellular tumors. Developmental Dynamics 239:45-55, 2010.

WNT-3A Regulates an Axin1/NRF2 Complex That Regulates Antioxidant Metabolism in Hepatocytes

“…It is, therefore, very interesting that at least in the liver it exerts a part of this function through the regulation of NRF2. Indeed, while WNT signaling has been demonstrated to regulate antioxidant metabolism through the b-Catenin-dependent upregulation of some antioxidant genes (13,35), it is now clear that it also targets the NRF2 signature. This is done in a b-Catenin-independent manner (Fig.…”

Chromatin occupancy of transcription factor 7-like 2 (TCF7L2) and its role in hepatic glucose metabolism

“…We cannot exclude the possibility that the robust changes in expression of genes involved in gluconeogenesis were part of a more global phenotypic shift in the hepatocytes, consistent with a role for TCF7L2 in metabolic zonation. The WNT/β-catenin pathway is a major determinant of the metabolic fate of hepatocytes [9,[38][39][40]. In this regard, several other pathways, including those responsible for amino acid, ammonia and drug metabolism, might also have been altered in our experimental model.…”

“…The potential link between TCF7L2 and hepatic glucose metabolism is further strengthened by increasing evidence of a key role for the WNT/β-catenin pathway in driving metabolic zonation in the liver [9]. Hepatocytes are metabolically specialised, depending partly on their position along the porto-central axis of the liver-cell plate [10].…”

Regulation of hepatocyte identity and quiescence

“…However, most activities display a gradient-like distribution throughout the porto-central axis and a dynamic fluctuation adjusting to the physiological state. A number of signals and mediators including oxygen, metabolites, hormones such as insulin and glucagon, nervous input, circadian signals and morphogens like WNT factors have been proposed [97,99,100]. These patterns are defined by the differential expression of the genes coding for the various zonated enzymes and are established postnatally, as zonation in mice is not observed earlier than in the first week after birth [101].…”