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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >Beta-catenin signaling in murine liver zonation and regeneration: A Wnt-Wnt situation!
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Beta-catenin signaling in murine liver zonation and regeneration: A Wnt-Wnt situation!

机译：β-catenin信号在鼠肝区带和再生中的作用：Wnt-Wnt的情况！

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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.
机译：肝脏特异性β-catenin敲除（β-Catenin-LKO）小鼠已揭示了β-catenin在代谢区带中的重要作用，该区带通过调节肝脏周围基因表达和部分肝切除（PH）后启动肝再生（LR） Cyclin-D1的表达。但是，在这些事件中调节β-catenin活性的因素仍然是一个谜。在这里，我们研究β-catenin激活在多大程度上依赖于Wnt信号传导以及Wnts的潜在细胞来源。我们研究了肝脏特异性Lrp5 / 6 KO（Lrp-LKO）小鼠，其中Wnt信号在肝细胞中被消除，而β-catenin基因保持完整。有趣的是，与β-catenin-LKO小鼠一样，Lrp-LKO在代谢区带中也表现出缺陷，这是由于缺乏谷氨酰胺合成酶（GS），Cyp1a2和Cyp2e1而引起的。由于缺乏β-catenin-TCF4缔合和缺乏Cyclin-D1，Lrp-LKO也显示出明显的LR延迟。为了解决肝脏中Wnt蛋白的来源，我们研究了条件性Wntless（Wls）KO小鼠，该小鼠缺乏从肝上皮细胞（Wls-LKO）或巨噬细胞（包括库普弗细胞（Wls-MKO））分泌Wnt的能力，或者内皮细胞（Wls-EKO）。虽然Wls-EKO具有胚胎致死性，但无法进一步分析成年肝脏的体内稳态和生长情况，但Wls-LKO和Wls-MKO可行，但未显示肝区带缺陷。 Wls-LKO显示LR正常启动。然而，Wls-MKO在LR中显示出明显但短暂的缺陷，这与β-catenin-TCF4缔合减少和Cyclin-D1表达减少有关。结论：Wnt信号传导是中枢肝细胞和LR期间β-catenin活性的主要上游效应物。肝细胞，胆管细胞或巨噬细胞不是调节肝区带的Wnt来源。但是，库普弗细胞是LR期间激活β-catenin所必需的Wnt分泌的主要来源。

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