Mammalian SIRT6 Is A Master Regulator Of Glucose Homeostasis

描述(申请人提供)：有效的葡萄糖代谢是维持细胞活力的关键。在正常的营养和氧气条件下，葡萄糖转化为丙酮酸，丙酮酸进入线粒体，用于氧化磷酸化产生ATP。在低氧或营养胁迫下，代谢切换到糖酵解，增加乳酸的产生，减少线粒体的呼吸。这种转换对于维持细胞在饥饿或低氧状态下是至关重要的；此外，最近的研究表明，在慢性葡萄糖失衡的情况下，例如在II型糖尿病患者中，调节这种转换可能是有益的。染色质是否在碳水化合物的流动中起作用还知之甚少。酵母Sir2蛋白是一种依赖于NAD的组蛋白去乙酰化酶，它可以感知细胞的代谢状态，并发挥染色质沉默的作用，以延长寿命和基因组稳定性。目前已发现7个哺乳动物Sir2同源基因(SIRT1-7)，但其功能尚未完全阐明。最近，我们发现哺乳动物的SIRT6是一种影响葡萄糖代谢和DNA修复的染色质因子。在小鼠中，SIRT6缺乏会引起严重的、致命的低血糖，最终导致加速死亡。在细胞水平上，SIRT6失活导致细胞葡萄糖摄取增加，乳酸产量增加，线粒体活性降低。初步结果表明，SIRT6是葡萄糖动态平衡的主调制子，调节这些代谢途径中几个关键基因的表达。在这种背景下，SIRT6似乎作为组蛋白H3赖氨酸9(H3K9)脱乙酰酶来抑制糖酵解基因的表达。这项提议的主要目标是具体测试SIRT6是否在体内调节营养应激，作为染色质修饰物来调节多个基因，这些基因参与将葡萄糖代谢从糖酵解转向线粒体呼吸。 与公共健康相关：为了在营养应激条件下生存，细胞触发适应性反应，改变葡萄糖的路线，以产生足够的能量来维持它们的生存。酵母蛋白Sir2作为生命周期的调节器，感知营养物质的供应以适应细胞的代谢活动；虽然最近的研究表明，一些哺乳动物同系物(称为sirtuins)在抗逆性和代谢动态平衡中发挥作用，但它们的确切分子功能仍未完全阐明。在这个提案中，我们将检验这样一个假设，即其中一个同系物SIRT6作为多个代谢基因的关键调节因子调节葡萄糖代谢，因此可能影响衰老和与衰老相关的疾病，如糖尿病和癌症。

DESCRIPTION (provided by applicant): Efficient glucose metabolism is critical for maintaining cellular viability. Under normal nutrient and oxygen conditions, glucose is converted to pyruvate, which enters the mitochondria to be used for oxidative phosphorylation to produce ATP. Under hypoxia or nutrient stress, metabolism is switched to glycolysis, increasing lactate production and reducing mitochondrial respiration. This switch is critical to maintain cells during periods of starvation or hypoxia; furthermore, recent studies indicate that modulating this switch could be beneficial under a situation of chronic glucose imbalance, such as in patients with Type II diabetes. Little is known whether chromatin plays a role in carbohydrate flux. The yeast Sir2 protein is an NAD-dependent histone deacetylase that senses the metabolic status of the cell and functions as a chromatin silencer to promote lifespan and genomic stability. Seven mammalian Sir2 homologs have been found (SIRT1-7), but their functions remain to be fully elucidated. Recently, we discovered that the mammalian SIRT6 is a chromatin factor that influences glucose metabolism and DNA repair. In mice, SIRT6-deficiency provokes a profound and lethal hypoglycemia which culminates in accelerated death. At the cellular level, SIRT6 inactivation leads to increased cellular glucose uptake, higher lactate production and decreased mitochondrial activity. Preliminary results indicate that SIRT6 is a master modulator of glucose homeostasis, regulating expression of several key genes in these metabolic pathways. In this context, SIRT6 appears to function as a histone H3 lysine9 (H3K9) deacetylase to inhibit expression of glycolytic genes. The main goal of this proposal is to test specifically whether SIRT6 regulates nutrient stress in vivo, functioning as a chromatin modifier to modulate multiple genes involved in switching glucose metabolism away of glycolysis and towards mitochondrial respiration. PUBLIC HEALTH RELEVANCE: In order to survive under conditions of nutrient stress, cells trigger an adaptive response, re-routing glucose in order to produce enough energy to sustain their survival. The yeast protein Sir2 functions as a modulator of lifespan, sensing nutrient availability to adapt the cellular metabolic activity; while recent studies indicate that some of the mammalian homologs (termed sirtuins) play a role in stress resistance and metabolic homeostasis, their precise molecular functions remain to be fully elucidated. In this proposal, we will test the hypothesis that one of these homologs, SIRT6, modulates glucose metabolism as a critical regulator of multiple metabolic genes, and as such might influence ageing and age related diseases like diabetes and cancer.