Potential conflict of interest: Dr. Williams received grants from Genentech.
Beta-catenin signaling in murine liver zonation and regeneration: A Wnt-Wnt situation!
Article first published online: 25 JUL 2014
© 2014 by the American Association for the Study of Liver Diseases
Volume 60, Issue 3, pages 964–976, September 2014
How to Cite
Yang, J., Mowry, L. E., Nejak-Bowen, K. N., Okabe, H., Diegel, C. R., Lang, R. A., Williams, B. O. and Monga, S. P. (2014), Beta-catenin signaling in murine liver zonation and regeneration: A Wnt-Wnt situation!. Hepatology, 60: 964–976. doi: 10.1002/hep.27082
Funded by NIH grants 1R01DK62277, 1R01DK100287 and Endowed Chair for Experimental Pathology to SPSM. This study was also in part funded by 5R01AR053293 and 5R21RR024887 to BOW.
- Issue published online: 25 AUG 2014
- Article first published online: 25 JUL 2014
- Accepted manuscript online: 20 FEB 2014 04:11AM EST
- Manuscript Accepted: 18 FEB 2014
- Manuscript Received: 23 NOV 2013
Liver-specific β-catenin knockout (β-Catenin-LKO) mice have revealed an essential role of β-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 β-catenin activity in these events remains an enigma. Here we investigate to what extent β-catenin activation is Wnt-signaling-dependent 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 β-catenin gene remained intact. Intriguingly, like β-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 β-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 β-catenin-TCF4 association and diminished Cyclin-D1 expression. Conclusion: Wnt-signaling is the major upstream effector of β-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 β-catenin activation during LR. (Hepatology 2014;60:964–976)