Molecular Mechanisms of Pancreatic Dysfunction Induced by Protein Malnutrition
Molecular Mechanisms of Pancreatic Dysfunction Induced by Protein Malnutrition
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DOI：
10.1053/j.gastro.2009.04.058
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发表时间：
2009-09-01
期刊：
影响因子：
29.4
通讯作者：
Williams, John A.
中科院分区：
文献类型：
--
作者：
Crozier, Stephen J.;D'Alecy, Louis G.;Williams, John A.
背景与目的：膳食蛋白质缺乏导致胰腺分泌大量营养素消化所需酶的能力下降。以前的工作表明，哺乳动物雷帕霉素靶蛋白（mTOR）通路的激素胆囊收缩素（CCK）的调制在正常的消化酶合成中起着重要的作用。本研究的目的是阐明mTOR在蛋白质缺乏诱导的胰腺功能障碍中的作用。方法：将野生型和CCK缺失小鼠喂食蛋白质缺乏的食物4天，然后允许在存在或不存在mTOR抑制剂雷帕霉素的情况下在对照食物上恢复。结果：饲喂低蛋白饲料后，胰腺的大小和分泌能力迅速下降。在野生型和CCK缺失小鼠中，重新喂食蛋白质充足的食物逆转了这些变化。胰腺大小的变化与消化酶含量和分泌的变化以及mTOR下游tat-gets的磷酸化有关。给予mTOR抑制剂雷帕霉素减少胰腺的再生，但不影响消化酶含量或分泌能力。结论：这些研究表明，膳食蛋白质调节胰腺生长，但不是消化酶的合成，通过CCK非依赖性激活的mTOR途径。
BACKGROUND & AIMS: Dietary protein deficiency results in diminished capacity of the pancreas to secrete enzymes needed for macronutrient digestion. Previous work has suggested that modulation of the mammalian target of rapamycin (mTOR) pathway by the hormone cholecystokinin (CCK) plays an important role in normal digestive enzyme synthesis after feeding. The purpose of this Study was to elucidate the role of mTOR in protein deficiency-induced pancreatic dysfunction. METHODS: Wild-type and CCK-null mice were fed protein-deficient chow for 4 days and then allowed to recover on control chow in the presence or absence of the mTOR inhibitor rapamycin. RESULTS: The size and secretory capacity of the pancreas rapidly decreased after feeding protein-deficient chow. Refeeding protein-replete chow reversed these changes in both wild-type and CCK-null mice. Changes in the size of the pancreas were paralleled by changes in the content and secretion of digestive enzymes, as well as the phosphorylation of downstream tat-gets of mTOR. Administration of the mTOR inhibitor rapamycin decreased regrowth of the pancreas but did not affect digestive enzyme content or secretory capacity. CONCLUSIONS: These studies demonstrate that dietary protein modulates pancreatic growth, but not digestive enzyme synthesis, via CCK-independent activation of the mTOR pathway.