The GCN2 eIF2α kinase regulates fatty-acid homeostasis in the liver during deprivation of an essential amino acid
The GCN2 eIF2α kinase regulates fatty-acid homeostasis in the liver during deprivation of an essential amino acid
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DOI：
10.1016/j.cmet.2007.01.001
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发表时间：
2007-02-01
期刊：
影响因子：
29
通讯作者：
Cavener, Douglas R.
中科院分区：
文献类型：
--
作者：
Guo, Feifan;Cavener, Douglas R.
需要代谢适应来应对蛋白质缺乏和营养不良的情况。 GCN2 eIF2 α 激酶是一种氨基酸缺乏的传感器，在酵母和哺乳动物调节氨基酸代谢（作为适应营养缺乏的一部分）方面发挥着关键作用。然而，人们对 GCN2 在哺乳动物适应长期氨基酸缺乏中的作用知之甚少。我们发现，在亮氨酸剥夺的野生型小鼠中，肝脏中脂肪生成基因的表达和脂肪酸合酶（FAS）的活性受到抑制，并且脂肪组织中的脂质储存被动员。相比之下，GCN2 缺陷小鼠出现肝脏脂肪变性，并表现出脂质动员减少。研究发现 Gcn2(-/-) 小鼠的肝脏脂肪变性是由脂肪生成基因（包括 Srebp-1c 和 Fas）的表达不受抑制引起的。因此，我们的研究确定了 GCN2 除了调节氨基酸代谢之外，在亮氨酸剥夺期间调节脂质代谢的新功能。
Metabolic adaptation is required to cope with episodes of protein deprivation and malnutrition. GCN2 eIF2 alpha kinase, a sensor of amino acid deficiency, plays a key role in yeast and mammals in modulating amino acid metabolism as part of adaptation to nutrient deprivation. The role of GCN2 in adaptation to long-term amino acid deprivation in mammals, however, is poorly understood. We found that expression of lipogenic genes and the activity of fatty acid synthase (FAS) in the liver are repressed and lipid stores in adipose tissue are mobilized in wildtype mice upon leucine deprivation. In contrast, GCN2-deficient mice developed liver steatosis and exhibited reduced lipid mobilization. Liver steatosis in Gcn2(-/-) mice was found to be caused by unrepressed expression of lipogenic genes, including Srebp-1c and Fas. Thus, our study identifies a novel function of GCN2 in regulating lipid metabolism during leucine deprivation in addition to regulating amino acid metabolism.