The Wnt signaling pathway effector TCF7L2 is upregulated by insulin and represses hepatic gluconeogenesis
The Wnt signaling pathway effector TCF7L2 is upregulated by insulin and represses hepatic gluconeogenesis
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DOI：
10.1152/ajpendo.00249.2012
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发表时间：
2012-11-01
影响因子：
5.1
通讯作者：
Jin, Tianru
中科院分区：
文献类型：
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作者：
Ip, Wilfred;Shao, Weijuan;Jin, Tianru
IP W，Shao W，Chiang YA，Jin T. Wnt信号通路效应效应TCF7L2被胰岛素上调并抑制肝糖生成。 Am J Physiol Endocrinol Metab 303：E1166-E1176，2012。首次发布于2012年9月11日； doi：10.1152/ajpendo.00249.2012。在转录因子7样2（TCF7L2）中确定单核苷酸多态性（SNP）与2型糖尿病的风险密切相关。 TCF7L2和β-catenin（beta-cat）在刺激Wnt靶基因表达中形成了二分转录因子CAT/TCF。 CAT/TCF还可以介导其他信号级联反应的效果，包括CAMP和胰岛素在细胞类型的特定方式中的效果。随着TCF7L2 2型糖尿病风险SNP的载体显示出肝葡萄糖的产生增加，我们旨在确定TCF7L2表达是否受养分可用性调节，以及TCF7L2和WNT是否调节肝糖原发生。我们检查了喂食后评估小鼠中肝的TCF7L2表达中的肝WNT活性，确定了胰岛素对TCF7L2表达和β-CAT SER（675）磷酸化的影响，并研究了Wnt活化和TCF7L2敲除对葡萄糖基因的作品的作用，并研究了glucone nocenic gene gene的作品。在topgal小鼠的腹膜肝细胞中观察到Wnt活性，而在人和小鼠肝细胞中检测到TCF7L2的表达。胰岛素和进食分别在体外和体内刺激肝TCF7L2表达。另外，胰岛素激活了β-cat Ser（675）磷酸化。腹膜内锂注射的Wnt激活在体内抑制了肝糖原性基因表达，而锂或Wnt-3a则降低了体外糖原性基因表达和肝细胞中体外的葡萄糖产生。在培养的肝细胞中，小型干扰RNA介导的TCF7L2敲低增加了葡萄糖的产生和糖原性基因表达。这些观察结果表明，Wnt信号传导和TCF7L2是肝糖异生的负调节剂，TCF7L2是肝细胞中胰岛素的下游效应子之一。
Ip W, Shao W, Chiang YA, Jin T. The Wnt signaling pathway effector TCF7L2 is upregulated by insulin and represses hepatic gluconeogenesis. Am J Physiol Endocrinol Metab 303: E1166-E1176, 2012. First published September 11, 2012; doi:10.1152/ajpendo.00249.2012.-Certain single nucleotide polymorphisms (SNPs) in transcription factor 7-like 2 (TCF7L2) are strongly associated with the risk of type 2 diabetes. TCF7L2 and beta-catenin (beta-cat) form the bipartite transcription factor cat/TCF in stimulating Wnt target gene expression. cat/TCF may also mediate the effect of other signaling cascades, including that of cAMP and insulin in cell-type specific manners. As carriers of TCF7L2 type 2 diabetes risk SNPs demonstrated increased hepatic glucose production, we aimed to determine whether TCF7L2 expression is regulated by nutrient availability and whether TCF7L2 and Wnt regulate hepatic gluconeogenesis. We examined hepatic Wnt activity in the TOPGAL transgenic mouse, assessed hepatic TCF7L2 expression in mice upon feeding, determined the effect of insulin on TCF7L2 expression and beta-cat Ser(675) phosphorylation, and investigated the effect of Wnt activation and TCF7L2 knockdown on gluconeogenic gene expression and glucose production in hepatocytes. Wnt activity was observed in pericentral hepatocytes in the TOPGAL mouse, whereas TCF7L2 expression was detected in human and mouse hepatocytes. Insulin and feeding stimulated hepatic TCF7L2 expression in vitro and in vivo, respectively. In addition, insulin activated beta-cat Ser(675) phosphorylation. Wnt activation by intraperitoneal lithium injection repressed hepatic gluconeogenic gene expression in vivo, whereas lithium or Wnt-3a reduced gluconeogenic gene expression and glucose production in hepatic cells in vitro. Small interfering RNA-mediated TCF7L2 knockdown increased glucose production and gluconeogenic gene expression in cultured hepatocytes. These observations suggest that Wnt signaling and TCF7L2 are negative regulators of hepatic gluconeogenesis, and TCF7L2 is among the downstream effectors of insulin in hepatocytes.