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首页> 外文期刊>American Journal of Physiology >The Wnt signaling pathway effector TCF7L2 is upregulated by insulin and represses hepatic gluconeogenesis
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The Wnt signaling pathway effector TCF7L2 is upregulated by insulin and represses hepatic gluconeogenesis

机译：Wnt信号通路效应子TCF7L2被胰岛素上调并抑制肝糖异生

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Certain single nucleotide polymorphisms (SNPs) in transcription factor 7-like 2 (TCF7L2) are strongly associated with the risk of type 2 diabetes. TCF7L2 and p-catenin (P-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 P-cat Ser~(675) phosphorylation, and investigated the effect of Wnt activation and TCF7L2 knockdown on gluconeogenic gene expression and glucose production in hepato-cytes. 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.
机译：转录因子7样2（TCF7L2）中的某些单核苷酸多态性（SNP）与2型糖尿病的风险密切相关。 TCF7L2和p-catenin（P-cat）在刺激Wnt靶基因表达时形成了双向转录因子cat / TCF，cat / TCF也可能以细胞类型特异性方式介导其他信号级联反应，包括cAMP和胰岛素的作用。由于TCF7L2 2型糖尿病风险SNP的携带者表现出肝葡萄糖生成增加，因此我们旨在确定TCF7L2表达是否受养分利用率调节以及TCF7L2和Wnt是否调节肝糖异生。我们检查了TOPGAL转基因小鼠的肝Wnt活性，评估了小鼠进食后肝TCF7L2的表达，确定了胰岛素对TCF7L2表达和P-cat Ser〜（675）磷酸化的影响，并研究了Wnt激活和TCF7L2敲除对小鼠的影响。肝细胞中糖异生基因表达和葡萄糖生成。在TOPGAL小鼠的中央肝细胞中观察到Wnt活性，而在人和小鼠的肝细胞中检测到TCF7L2表达。胰岛素和喂养分别在体外和体内刺激了肝TCF7L2表达。此外，胰岛素激活了β-catSer〜（675）磷酸化。腹膜内注射锂激活Wnt体内抑制肝糖原异生基因表达，而锂或Wnt-3a降低体外肝细胞中糖原异生基因表达和葡萄糖生成。小干扰RNA介导的TCF7L2敲低增加了培养的肝细胞中葡萄糖的产生和糖异生基因的表达。这些观察结果表明，Wnt信号和TCF7L2是肝糖异生的负调节剂，而TCF7L2是肝细胞中胰岛素的下游效应子。

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