Wnt signaling in liver homeostasis and regeneration

β‐catenin plays a critical role in liver homeostasis and during liver regeneration (LR). Numerous pathways can activate β‐catenin, the primary one being Wnt signaling. In this study we investigated the source of Wnts and to what extent β‐catenin signaling in liver is Wnt‐dependent. LRP5/6 are the co‐receptors for Wnts. We generated hepatocyte specific LRP5/6 double knockout mice (KO1) where Wnt‐signaling was abolished while Wnt‐independent signaling can still activate β‐catenin, and compared KO1 with hepatocyte specific β‐catenin knockout mice (KO2). We found that KO1 phenocopied KO2 in defective hepatic zonation and delay in LR. β‐catenin activation was impaired after partial hepatectomy (PH) in KO1 due to the lack of Wnt‐signaling. Given the importance of Wnt‐signaling in LR, we further investigated the source of Wnts. Evenness interrupted (Evi) regulates Wnt secretion. We generated hepatocyte specific Evi knockout mice (KO3), which lack the ability of hepatocytes to secrete Wnts. KO3 had normal hepatic zonation and initiation of LR; however, KO3 had sustained proliferation after PH at 72 & 96h. In WT, we found an induction of Wnt5a along with an increase in ROR2, an inhibitor of β‐catenin signaling, which is absent in KO3. Our study suggests that Wnt‐signaling is the major determinant controlling β‐ catenin activation in liver. Further, hepatocytes are not the source of canonical Wnts that activate β‐catenin, but rather produce noncanonical Wnt5a that terminates β‐catenin signaling during late LR.