Beta-Catenin Signaling in Murine Liver Zonation and Regeneration: A Wnt-Wnt Situation!

Liver-specific beta-catenin knockout (beta-catenin-LKO) mice have revealed an essential role of beta-catenin in metabolic zonation where it regulates pericentral gene expression and in initiating liver regeneration (LR) after partial hepatectomy (PH), by regulating expression of Cyclin-D1. However, what regulates beta-catenin activity in these events remains an enigma. Here we investigate to what extent beta-catenin activation is Wnt-signalingdependent and the potential cell source of Wnts. We studied liver-specific Lrp5/6 KO (Lrp-LKO) mice where Wnt-signaling was abolished in hepatocytes while the beta-catenin gene remained intact. Intriguingly, like beta-catenin-LKO mice, Lrp-LKO exhibited a defect in metabolic zonation observed as a lack of glutamine synthetase (GS), Cyp1a2, and Cyp2e1. Lrp-LKO also displayed a significant delay in initiation of LR due to the absence of beta-catenin-TCF4 association and lack of Cyclin-D1. To address the source of Wnt proteins in liver, we investigated conditional Wntless (Wls) KO mice, which lacked the ability to secrete Wnts from either liver epithelial cells (Wls-LKO), or macrophages including Kupffer cells (Wls-MKO), or endothelial cells (Wls-EKO). While Wls-EKO was embryonic lethal precluding further analysis in adult hepatic homeostasis and growth, Wls-LKO and Wls-MKO were viable but did not show any defect in hepatic zonation. Wls-LKO showed normal initiation of LR; however, Wls-MKO showed a significant but temporal deficit in LR that was associated with decreased beta-catenin-TCF4 association and diminished Cyclin-D1 expression. Conclusion: Wnt-signaling is the major upstream effector of beta-catenin activity in pericentral hepatocytes and during LR. Hepatocytes, cholangiocytes, or macrophages are not the source of Wnts in regulating hepatic zonation. However, Kupffer cells are a major contributing source of Wnt secretion necessary for beta-catenin activation during LR.