Role of the mTOR complex 1 pathway in the in vivo maintenance of the intestinal mucosa by oral intake of amino acids
Role of the mTOR complex 1 pathway in the in vivo maintenance of the intestinal mucosa by oral intake of amino acids
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DOI：
10.1111/j.1447-0594.2011.00729.x
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发表时间：
2012-01-01
影响因子：
3.3
通讯作者：
Yokono, Koichi
中科院分区：
文献类型：
--
作者：
Nakamura, Akira;Hara, Kenta;Yokono, Koichi
目的：老年、多病患者的口服营养素摄入经常受到影响，但肠外营养会导致肠道萎缩，损害肠道功能。为了揭示氨基酸参与肠道萎缩和恢复的分子机制，我们研究了雷帕霉素敏感的机制靶点雷帕霉素(MTOR)复合体1(MTORC1)通路是否参与了这一过程。方法：C57BL/6N小鼠单独饲喂葡萄糖溶液、葡萄糖加氨基酸溶液或正常饮食不同时间。制备小鼠小肠切片，对绒毛高度和绒毛密度进行量化。通过免疫染色和免疫印迹分析核糖体S6蛋白(S6)的磷酸化情况，作为mTORC1途径的读数。为了证实mTORC1途径的作用，检测了特异性mTOR抑制剂雷帕霉素的抑制作用。结果：在只喂葡萄糖的小鼠中，诱导禁食导致时间依赖性的肠粘膜萎缩，而补充氨基酸则保护肠粘膜免受萎缩。只喂食葡萄糖的小鼠肠黏膜中S6的磷酸化降低，而补充氨基酸则增加了S6的磷酸化。重要的是，腹腔注射雷帕霉素减弱了氨基酸对肠粘膜的保护作用，其机制与减少S6磷酸化的模式一致。结论：mTORC1途径在口服氨基酸对肠粘膜的体内维持中起着关键作用。Geriatr Gerontol Int 2012；12：131-139。
Aim: Oral intake of nutrients is often compromised in elderly, multimorbid patients, but parenteral nutrition causes intestinal atrophy and impairs intestinal function. To uncover the molecular mechanisms by which amino acids are involved in intestinal atrophy and recovery, we studied whether the rapamycin-sensitive mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) pathway is involved in this process.Methods: C57BL/6N mice were fed a glucose solution alone, glucose solution with amino acids or normal chow diet for various lengths of time. Intestinal sections were prepared from these mice and the villus height and villus density were quantified. As a readout for the mTORC1 pathway, the phosphorylation of the ribosomal S6 protein (S6) was analyzed by immunostaining and immunoblotting. To confirm the role of the mTORC1 pathway, the inhibitory effect of a specific mTOR inhibitor, rapamycin, was examined.Results: Inducing fasting in mice fed only glucose caused time-dependent intestinal mucosal atrophy, whereas supplementation with amino acids protected the intestinal mucosa from atrophy. Phosphorylation of S6 decreased in the intestinal mucosa of mice fed only glucose, whereas supplementation with amino acids increased S6 phosphorylation. Importantly, intraperitoneal injection of rapamycin attenuated the protective effect of amino acids on the intestinal mucosa in a pattern consistent with the decrease of S6 phosphorylation.Conclusions: These results indicate that the mTORC1 pathway plays a crucial role in the in vivo maintenance of the intestinal mucosa by the oral intake of amino acids. Geriatr Gerontol Int 2012; 12: 131-139.