Yi Fenghua, Sun Jane, Lim Gareth E, Fantus I George, Brubaker Patricia L, Jin Tianru
Division of Cell and Molecular Biology, Toronto General Research Institute, University Health Network, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada M5G 1L7.
Endocrinology. 2008 May;149(5):2341-51. doi: 10.1210/en.2007-1142. Epub 2008 Feb 7.
The proglucagon gene (glu) encodes the incretin hormone glucagon-like peptide-1 (GLP-1), produced in the intestinal endocrine L cells. We found previously that the bipartite transcription factor beta-catenin/T cell factor (cat/TCF), the major effector of the canonical Wnt signaling pathway, activates intestinal glu expression and GLP-1 production. We show here that 100 nm insulin stimulated glu expression and enhanced GLP-1 content in the intestinal GLUTag L cell line as well as in primary fetal rat intestinal cell cultures. Increased intestinal glu mRNA expression and GLP-1 content were also observed in vivo in hyperinsulinemic MKR mice. In the GLUTag cells, insulin-induced activation of glu expression occurred through the same TCF site that mediates cat/TCF activation. Phosphatidylinositol 3-kinase inhibition, but not protein kinase B inhibition, attenuated the stimulation by insulin. Furthermore, nuclear beta-catenin content in the intestinal L cells was increased by insulin. Finally, insulin enhanced the binding of TCF-4 and beta-catenin to the TCF site in the glu promoter G2 enhancer element, as determined by quantitative chromatin immunoprecipitation assay. Collectively, these findings indicate that enhancement of beta-catenin nuclear translocation and cat/TCF binding are among the mechanisms underlying cross talk between the insulin and Wnt signaling pathways in intestinal endocrine L cells.
胰高血糖素原基因（glu）编码肠促胰岛素激素胰高血糖素样肽-1（GLP-1），由肠道内分泌L细胞产生。我们之前发现，作为经典Wnt信号通路主要效应器的双组分转录因子β-连环蛋白/T细胞因子（cat/TCF）可激活肠道glu表达并促进GLP-1生成。我们在此表明，100 nM胰岛素可刺激肠道GLUTag L细胞系以及原代胎鼠肠道细胞培养物中的glu表达，并增加GLP-1含量。在高胰岛素血症的MKR小鼠体内也观察到肠道glu mRNA表达和GLP-1含量增加。在GLUTag细胞中，胰岛素诱导的glu表达激活是通过介导cat/TCF激活的相同TCF位点发生的。磷脂酰肌醇3-激酶抑制而非蛋白激酶B抑制可减弱胰岛素的刺激作用。此外，胰岛素可增加肠道L细胞中核β-连环蛋白的含量。最后，通过定量染色质免疫沉淀分析确定，胰岛素增强了TCF-4和β-连环蛋白与glu启动子G2增强子元件中TCF位点的结合。总的来说，这些发现表明，β-连环蛋白核转位增强和cat/TCF结合是肠道内分泌L细胞中胰岛素和Wnt信号通路之间相互作用的潜在机制。
