Rapamycin inhibits liver growth during refeeding in rats via control of ribosomal protein translation but not cap-dependent translation initiation
Rapamycin inhibits liver growth during refeeding in rats via control of ribosomal protein translation but not cap-dependent translation initiation
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DOI：
10.1093/jn/136.1.27
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发表时间：
2006-01-01
影响因子：
4.2
通讯作者：
Gruppuso, PA
中科院分区：
文献类型：
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作者：
Anand, P;Gruppuso, PA
我们研究了哺乳动物雷帕霉素靶蛋白（mTOR）在肝细胞生长中的作用。为了将细胞生长与细胞增殖分离，我们采用了大鼠非增殖性肝脏生长的体内模型，在48小时的食物剥夺后重新喂养。饥饿导致肝脏质量，肝脏蛋白质和细胞大小的减少，所有这些都在很大程度上恢复后24小时的再喂养。在再喂养期之前给予mTOR抑制剂雷帕霉素部分抑制了肝脏蛋白含量的恢复。再喂养也与核糖体蛋白S6磷酸化和真核起始因子（eIF）4 E结合蛋白1（4 E-BP 1）磷酸化的增加相关。4 E-BP 1磷酸化伴随着含有4 E-BP 1与eIF 4 E的复合物的丰度的降低。这些变化被雷帕霉素给药所阻止。然而，eIF 4 E和eIF 4G和eIF 2 α磷酸化的结合，两者都是通过再喂养刺激的，对雷帕霉素不敏感。这些观察结果的功能重要性通过多核糖体分离证实，其显示编码核糖体蛋白的含有5'寡嘧啶片段的mRNA的翻译起始被雷帕霉素抑制，而帽依赖性mRNA的信号转导和转录激活因子1（STAT-1）的翻译不受影响。在对照组和注射雷帕霉素的大鼠中，再喂养期间核糖体蛋白的丰度超过总蛋白含量。我们的结论是，在再喂养过程中的肝蛋白的增生是依赖于mTOR介导的激活核糖体蛋白的翻译，但不依赖于mTOR介导的激活帽依赖性翻译起始。
We examined the role of the mammalian target of rapamycin (mTOR) in hepatic cell growth. To dissociate cell growth from cell proliferation, we employed an in vivo model of nonproliferative liver growth in rats, refeeding after 48 h of food deprivation. Starvation resulted in a decrease in liver mass, liver protein, and cell size, all of which were largely restored after 24 h of refeeding. Administration of the mTOR inhibitor, rapamycin, before the refeeding period partially inhibited the restoration of liver protein content. Refeeding was also associated with an increase in ribosomal protein S6 phosphorylation and phosphorylation of the eukaryotic initiation factor (elF) 4E binding protein 1 (4E-BP1). 4E-BP1 phosphorylation was accompanied by a decrease in the abundance of the complex containing 4E-BP1 with elF4E. These changes were prevented by rapamycin administration. However, association of elF4E and elF4G and elF2 alpha phosphorylation, both of which are stimulated by refeeding, were insensitive to rapamycin. The functional importance of these observations was confirmed by polysome fractionation, which showed that translation initiation of 5' oligopyrimidine tract-containing mRNAs, which encode ribosomal proteins, was inhibited by rapamycin, whereas translation of signal transducer and activator of transcription 1 (STAT-1), a cap-dependent mRNA, was unaffected. The abundance of ribosomal proteins paralleled total protein content during refeeding in both control and rapamycin-injected rats. We conclude that accretion of liver protein during refeeding is dependent on mTOR-mediated activation of the translation of ribosomal proteins but not dependent on mTOR-mediated activation of cap-dependent translation initiation.