β-catenin signaling in murine liver zonation and regeneration: a Wnt-Wnt situation!
β-catenin signaling in murine liver zonation and regeneration: a Wnt-Wnt situation!
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DOI：
10.1002/hep.27082
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发表时间：
2014-09
期刊：
影响因子：
13.5
通讯作者：
Monga, Satdarshan P.
中科院分区：
文献类型：
--
作者：
Yang, Jing;Mowry, Laura E.;Nejak-Bowen, Kari Nichole;Okabe, Hirohisa;Diegel, Cassandra R.;Lang, Richard A.;Williams, Bart O.;Monga, Satdarshan P.
肝脏特异性β-连环蛋白敲除（β-连环蛋白-LKO）小鼠已经揭示了β-连环蛋白在代谢分区中的重要作用，其中其通过调节细胞周期蛋白-D1的表达来调节中心周围基因表达和在部分肝切除术（PH）后启动肝再生（LR）。然而，在这些事件中是什么调节β-连环蛋白活性仍然是一个谜。在这里，我们研究β-catenin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Lrp 5/6 KO（Lrp-LKO）小鼠，其中肝细胞中的Wnt信号被消除，而β-连环蛋白基因保持完整。有趣的是，与β-连环蛋白-LKO小鼠一样，Lrp-LKO表现出代谢分区缺陷，观察到缺乏谷氨酰胺合成酶（GS）、Cyp 1a 2和Cyp 2 e1。Lrp-LKO还显示由于缺乏β-连环蛋白-TCF 4缔合和缺乏细胞周期蛋白-D1而显著延迟LR的启动。为了解决肝脏中Wnt蛋白的来源，我们研究了条件性Wnt无（Wls）KO小鼠，其缺乏从肝上皮细胞（Wls-LKO）或巨噬细胞（包括枯否细胞（Wls-MKO））或内皮细胞（Wls-EKO）分泌Wnt的能力。虽然Wls-EKO是胚胎致死的，排除了对成年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显示正常的LR起始，然而Wls-MKO显示LR中显著但暂时的缺陷，其与β-连环蛋白-TCF 4结合减少和细胞周期蛋白-D1表达减少相关。Wnt信号传导是中央周围肝细胞和LR期间β-连环蛋白活性的主要上游效应物。肝细胞、胆管细胞或巨噬细胞不是Wnt调节肝脏分区的来源。然而，枯否细胞是LR期间β-连环蛋白活化所必需的Wnt分泌的主要贡献来源。
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 lack of glutamine synthetase (GS), Cyp1a2 and Cyp2e1. Lrp-LKO also displayed a significant delay in initiation of LR due to 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 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. 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.
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影响因子：
24.1
作者：
Nikolic, Tatjana;Movita, Dowty;Hendriks, Rudi
通讯作者：
Hendriks, Rudi
过度表达丝氨酸 45 突变体 β-连环蛋白的小鼠加速肝再生和肝癌发生。
影响因子：
13.5
作者：
Nejak-Bowen, Kari N.;Thompson, Michael D.;Singh, Sucha;Bowen, William C., Jr.;Dar, Mohd Jamal;Khillan, Jaspal;Dai, Chunsun;Monga, Satdarshan P. S.
通讯作者：
Monga, Satdarshan P. S.
影响因子：
5.8
作者：
Michalopoulos, George K.
通讯作者：
Michalopoulos, George K.
影响因子：
3
作者：
Clausen, BE;Burkhardt, C;Förster, I
通讯作者：
Förster, I
影响因子：
6
作者：
Apte, Udayan;Singh, Sucha;Monga, Satdarshan P. S.
通讯作者：
Monga, Satdarshan P. S.