Mechanisms of activation of mouse and human enteroendocrine cells by nutrients.
Mechanisms of activation of mouse and human enteroendocrine cells by nutrients.
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DOI：
10.1136/gutjnl-2014-306834
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发表时间：
2015-04
期刊：
影响因子：
24.5
通讯作者：
Blackshaw LA
中科院分区：
文献类型：
--
作者：
Symonds EL;Peiris M;Page AJ;Chia B;Dogra H;Masding A;Galanakis V;Atiba M;Bulmer D;Young RL;Blackshaw LA
当营养素刺激肠内分泌细胞（EEC）释放肠道激素时，抑制食物摄入和葡萄糖稳态都得到促进。几种特定的营养素受体可能位于EEC上，对膳食糖、氨基酸和脂肪酸作出反应。肥胖和II型糖尿病的旁路手术通过将营养物质分流到远端肠道来起作用，在那里它增加了营养受体的激活和介质释放，但激活的细胞机制在很大程度上是未知的。我们确定了哪些营养素受体在小鼠和人类的哪些肠道区域和哪些细胞中表达，它们如何与不同类型的EEC相关，它们如何被激活导致激素和5-HT释放。通过定量PCR评估了17种营养素受体和EEC介质的mRNA表达，并在整个小鼠和人肠道上皮中发现。出现了许多物种的相似性，特别是在远端肠道中的几种受体的密集表达。免疫标记显示受体与EEC介质PYY和GLP-1（L-细胞）或5-HT（肠嗜铬细胞）的特异性共定位。我们暴露离体近端结肠粘膜特定的营养物质，招募特定的EEC细胞外受体调节激酶（p-ERK）和钙调蛋白激酶II（pCAMKII）内的信号通路，如随后的免疫标记所示，并激活这些介质的释放。芳香族氨基酸在小鼠中激活了这两种途径，但在人类中，它们仅诱导pCAMKII，其主要与5-HT表达共定位。激活对百日咳毒素敏感。脂肪酸（C12）在所有EEC类型中有效激活人体中的p-ERK，并诱发所有三种介质的有效释放。特定的营养素受体与EEC内不同的激活途径相关。这些可能为肥胖和II型糖尿病的干预提供离散的互补药理学靶点。
Inhibition of food intake and glucose homeostasis are both promoted when nutrients stimulate enteroendocrine cells (EEC) to release gut hormones. Several specific nutrient receptors may be located on EEC that respond to dietary sugars, amino acids and fatty acids. Bypass surgery for obesity and type II diabetes works by shunting nutrients to the distal gut, where it increases activation of nutrient receptors and mediator release, but cellular mechanisms of activation are largely unknown. We determined which nutrient receptors are expressed in which gut regions and in which cells in mouse and human, how they are associated with different types of EEC, how they are activated leading to hormone and 5-HT release. mRNA expression of 17 nutrient receptors and EEC mediators was assessed by quantitative PCR and found throughout mouse and human gut epithelium. Many species similarities emerged, in particular the dense expression of several receptors in the distal gut. Immunolabelling showed specific colocalisation of receptors with EEC mediators PYY and GLP-1 (L-cells) or 5-HT (enterochromaffin cells). We exposed isolated proximal colonic mucosa to specific nutrients, which recruited signalling pathways within specific EEC extracellular receptor-regulated kinase (p-ERK) and calmodulin kinase II (pCAMKII), as shown by subsequent immunolabelling, and activated release of these mediators. Aromatic amino acids activated both pathways in mouse, but in humans they induced only pCAMKII, which was colocalised mainly with 5-HT expression. Activation was pertussis toxin-sensitive. Fatty acid (C12) potently activated p-ERK in human in all EEC types and evoked potent release of all three mediators. Specific nutrient receptors associate with distinct activation pathways within EEC. These may provide discrete, complementary pharmacological targets for intervention in obesity and type II diabetes.
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影响因子：
7.1
作者：
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