Regulation of Fat Metabilism Induced by Amino Acid Deprivation

项目摘要 营养不良和营养匮乏是人类最大的致病因素 死亡率和对疾病的严重程度和易感性有着深远的影响。氨基酸 蛋白质缺乏是人类最常见的营养不良形式。我们 发现缺乏必需的氨基酸对脂肪有深远的影响 抑制肝脏脂肪合成并导致脂肪组织丢失的代谢 导致内脏脂肪储存完全耗尽。对被剥夺权利的反应 必需氨基酸亮氨酸模拟饥饿反应，并受氨基酸调节 酸传感器GCN2 eIF2α激酶。最近，我们发现GCN2是必需的 在禁食期间抑制生脂和生脂基因的表达。我们建议 为了研究GCN2抑制SREBPs表达的机制， 肝脏脂肪生成和胆固醇生成的关键调节因子。要比较的研究 对禁食和肝脏中单一必需氨基酸缺乏的适应将是 为确定共有和不同的调控途径而进行。同时， 对由必需氨基酸耗尽引起的内脏脂肪损失的调节将是 探讨GCN2在控制脂肪酸氧化中的作用 在营养匮乏期间。

Project Summary Malnutrition and nutrient deprivation are the single largest contributors to human mortality and profoundly impacts the severity and susceptibility to diseases. Amino acid and protein deprivation is the most common form of malnutrition in humans. We discovered that deprivation of essential amino acids has a profound impact on fat metabolism by repressing fat synthesis in the liver and inducing the loss of adipose tissue resulting in the complete depletion visceral fat stores. The response to deprivation of the essential amino acid leucine mimics a starvation response and is regulated by the amino acid sensor GCN2 eIF2 alpha kinase. More recently we discovered that GCN2 is required to repress both lipogenic and cholesterogenic gene expression during fasting. We propose to investigate the mechanism of whereby GCN2 represses the expression of the SREBPs, the key regulators of hepatic lipogenesis and cholesterogenesis. Studies to compare adaptation to fasting and deprivation of single essential amino acids in the liver will be conducted to determine shared and divergent regulatory pathways. In parallel, the regulation of loss of visceral fat, induced by depletion of essential amino acids, will be investigated to determine the role of GCN2 in controlling the oxidation of fatty acids during nutrient deprivation.