小鼠肝脏分区和再生中的 β-连环蛋白信号传导：Wnt-Wnt 情况！,Hepatology

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小鼠肝脏分区和再生中的 β-连环蛋白信号传导：Wnt-Wnt 情况！
Hepatology ( IF 12.9 ) Pub Date : 2014-07-25 , DOI: 10.1002/hep.27082
Jing Yang ₁ , Laura E. Mowry ₂ , Kari Nichole Nejak-Bowen ₁ , Hirohisa Okabe ₁ , Cassandra R. Diegel ₂ , Richard A. Lang ₃ , Bart O. Williams ₂ , Satdarshan P. Monga _{1,

4}

Affiliation

肝脏特异性 β-连环蛋白敲除 (β-Catenin-LKO) 小鼠揭示了 β-连环蛋白在代谢区带中的重要作用，它通过调节周围中心基因表达和启动肝部分切除术 (PH) 后的肝再生 (LR) Cyclin-D1 的表达。然而，在这些事件中调节 β-catenin 活性的因素仍然是一个谜。在这里，我们研究了 β-连环蛋白激活在多大程度上是 Wnt 信号依赖性的，以及 Wnt 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 表现出代谢区带缺陷，观察到缺乏谷氨酰胺合成酶 (GS)、Cyp1a2 和 Cyp2e1。由于缺乏 β-catenin-TCF4 结合和 Cyclin-D1，Lrp-LKO 也显示出 LR 启动的显着延迟。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，它们缺乏从肝上皮细胞 (Wls-LKO) 或包括库普弗细胞 (Wls-MKO) 在内的巨噬细胞分泌 Wnt 的能力，或内皮细胞（Wls-EKO）。虽然 Wls-EKO 是胚胎致死的，排除了对成人肝脏稳态和生长的进一步分析，但 Wls-LKO 和 Wls-MKO 是可行的，但在肝脏分区中没有显示任何缺陷。Wls-LKO 显示 LR 的正常启动；然而，Wls-MKO 在 LR 中显示出显着但暂时的缺陷，这与 β-catenin-TCF4 关联减少和 Cyclin-D1 表达减少有关。结论：Wnt 信号是中央肝细胞周围和 LR 期间 β-连环蛋白活性的主要上游效应器。肝细胞、胆管细胞或巨噬细胞不是调节肝分区的 Wnt 来源。然而，库普弗细胞是 LR 期间 β-连环蛋白激活所必需的 Wnt 分泌的主要来源。（肝病学 2014；60：964–976）

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Beta-catenin signaling in murine liver zonation and regeneration: A Wnt-Wnt situation!

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)

更新日期：2014-07-25

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