通过IR / IRS / PI3K / Akt途径通过细胞外谷氨酸诱导的mTORC1活化增强了猪肠道干细胞的扩增,Journal of Agricultural and Food Chemistry

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通过IR / IRS / PI3K / Akt途径通过细胞外谷氨酸诱导的mTORC1活化增强了猪肠道干细胞的扩增
Journal of Agricultural and Food Chemistry ( IF 5.7 ) Pub Date : 2019-08-06 00:00:00 , DOI: 10.1021/acs.jafc.9b03626
Min Zhu ₁ , Ying-chao Qin ₁ , Chun-qi Gao ₁ , Hui-chao Yan ₁ , Xiang-guang Li ₂ , Xiu-qi Wang ₁

Affiliation

谷氨酸（Glu）是肠道上皮稳态的关键营养调节剂。此外，隐窝基底的肠干细胞（ISC）在维持肠上皮的更新和体内平衡方面起着重要作用，而Glu和ISC之间的通讯方面仍然未知。在这里，我们确定Glu和雷帕霉素复合物1（mTORC1）的哺乳动物目标是ISC扩展的基本调节剂。结果表明，细胞外Glu促进了ISC扩展，这由增加的肠类器官形成效率和出芽效率以及细胞增殖标志物Ki67免疫荧光和分化标志物角蛋白20（KRT20）的表达所表明。而且，在ISC中，介导胰岛素受体底物（IRS）磷酸化的胰岛素受体（IR）和下游信号转磷酸肌醇3-激酶（PI3K）/蛋白激酶B（Akt）途径参与了该反应。如预期的那样，在肠猪肠上皮细胞系（IPEC-J2）中观察到Glu诱导的mTORC1信号激活，并且Glu激活了PI3K / Akt / mTORC1途径。因此，PI3K抑制部分抑制Glu诱导的mTORC1激活。另外，Glu增加IR和IRS的磷酸化水平，并抑制IR下调IRS / PI3K / Akt途径。总的来说，我们的发现首先表明细胞外Glu通过IR / IRS / PI3K / Akt途径激活mTORC1并刺激ISC扩增，为调节肠上皮的生长和健康提供了新的视角。

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Extracellular Glutamate-Induced mTORC1 Activation via the IR/IRS/PI3K/Akt Pathway Enhances the Expansion of Porcine Intestinal Stem Cells

Glutamate (Glu) is a critical nutritional regulator of intestinal epithelial homeostasis. In addition, intestinal stem cells (ISCs) at crypt bases are known to play important roles in maintaining the renewal and homeostasis of the intestinal epithelium, and the aspects of communication between Glu and ISCs are still unknown. Here, we identify Glu and mammalian target of rapamycin complex 1 (mTORC1) as essential regulators of ISC expansion. The results showed that extracellular Glu promoted ISC expansion, indicated by increased intestinal organoid forming efficiency and budding efficiency as well as cell proliferation marker Ki67 immunofluorescence and differentiation marker Keratin 20 (KRT20) expression. Moreover, the insulin receptor (IR) mediating phosphorylation of the insulin receptor substrate (IRS) and downstream signaling phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway was involved in this response in ISCs. As expected, Glu-induced mTORC1 signaling activation was observed in the intestinal porcine enterocyte cell line (IPEC-J2), and Glu activated the PI3K/Akt/mTORC1 pathway. Accordingly, PI3K inhibition partially suppressed Glu-induced mTORC1 activation. In addition, Glu increased the phosphorylation levels of IR and IRS, and inhibiting IR downregulated the IRS/PI3K/Akt pathway. Collectively, our findings first indicate that extracellular Glu activates mTORC1 via the IR/IRS/PI3K/Akt pathway and stimulates ISC expansion, providing a new perspective for regulating the growth and health of the intestinal epithelium.

更新日期：2019-08-06

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