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Beta‐catenin signaling in murine liver zonation and regeneration: A Wnt‐Wnt situation!
Author(s) -
Yang Jing,
Mowry Laura E.,
NejakBowen Kari Nichole,
Okabe Hirohisa,
Diegel Cassandra R.,
Lang Richard A.,
Williams Bart O.,
Monga Satdarshan P.
Publication year - 2014
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.27082
Subject(s) - wnt signaling pathway , biology , cyclin d1 , lrp6 , axin2 , beta catenin , liver regeneration , lrp5 , microbiology and biotechnology , catenin , medicine , endocrinology , regeneration (biology) , signal transduction , cell cycle , cell , genetics
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. (H epatology 2014;60:964–976)