Amino Acids-Rab1A Nutrient Signaling in the Regulation of Glucose Homeostasis

氨基酸（AAs）是生命的基本组成部分和燃料。它们也越来越被认为是调节生长和代谢过程的化学信号。越来越多的证据清楚地表明，AA传感和信号传导在健康和疾病中起着关键作用。mTOR是AA感测和信号传导的主要调节剂。最近的进展导致了对AA如何激活mTOR的一些基本理解。Rag是一种锚定在溶酶体上的异二聚体小GTdR，显示出响应于AA刺激而激活mTOR。令人惊讶的是，我们和其他人发现AA仍然可以在Rag敲除的酵母和小鼠中激活mTOR，这表明存在另一种AA信号传导机制。在最近发表的研究中，我们进行了酵母遗传筛选并鉴定了Rab 1A，一种位于ER/高尔基体上的小GTdR，代表酵母和哺乳动物中mTOR上游AA信号传导的新的保守介体（托马斯et al.，Cancer Cell 26：754）。迄今为止，AA-Rab 1A信号传导的生理功能尚不清楚。因此，我们在年轻的成年小鼠中产生了他莫昔芬诱导的全身Rab 1A敲除。Rab 1A基因敲除动物除表现出高血糖和葡萄糖耐受不良外，其他相对正常。进一步的分析表明，突变动物具有显著较小的β细胞质量，并且它们的β细胞经历向α细胞的转分化。此外，Rab 1A基因敲除胰腺β细胞中胰岛素mRNA和蛋白表达均显著降低。一致地，我们进一步表明AA-Rab 1A信号调节β细胞系中的胰岛素转录。基于这些初步结果，我们提出了测试的假设，β细胞自主AA-Rab 1A信号通过调节胰岛素转录，β细胞增殖和维持在哺乳动物中控制葡萄糖稳态。我们将使用细胞和基因工程小鼠模型在正常生理和病理条件下剖析基本机制和意义。如果成功的话，这个项目将提高关于营养素如何控制全身葡萄糖稳态的基本知识。它还可能为糖尿病、癌症和其他相关疾病的营养和/或治疗干预带来新的机会。

Amino acids (AAs) are basic building blocks and fuels of life. They are also increasingly appreciated as chemical signals that regulate growth and metabolic processes. Accumulating evidence clearly show that AA sensing and signaling play a critical role in health and diseases. mTOR is a master regulator of AA sensing and signaling. Recent progress has led to some basic understanding of how AA activates mTOR. Rag, a heterodimeric small GTPase anchored on the lysosomes, was shown to activate mTOR in response to AA stimulation. Surprisingly, we and others found that AAs can still activate mTOR in Rag-knockout yeast and mice, indicating that an alternative AA signaling mechanism exists. In a recently published study, we carried out a yeast genetic screening and identified Rab1A, a small GTPase localized on the ER/Golgi, represents a novel, conserved mediator of AA signaling upstream of mTOR in yeast and mammals (Thomas et al., Cancer Cell 26:754). To date, the physiological functions of AA-Rab1A signaling are not known. Therefore, we generated tamoxifen- induced whole body Rab1A knockout in young adult mice. Rab1A knockout animals were relatively normal except exhibiting hyperglycemia and glucose intolerance. Further analysis showed that the mutant animals had significantly smaller β-cell mass and their β-cells underwent trans-differentiation to α-cells. Moreover, both insulin mRNA and protein expression were markedly reduced in Rab1A knockout pancreatic β-cells. Consistently, we further showed that AA-Rab1A signaling regulated insulin transcription in β-cell lines. Based on these preliminary results, we propose to test the hypothesis that β-cell-autonomous AA-Rab1A signaling controls glucose homeostasis by regulating insulin transcription, β-cell proliferation and maintenance in mammals. We will dissect the basic mechanisms and significance under normal physiological and pathological conditions using cell and genetically engineered mouse models. If successful, this project will enhance the basic knowledge on how nutrients control whole body’s glucose homeostasis. It could also lead to new opportunities for nutritional and/or therapeutic intervention for diabetes, cancer and other related diseases.