Mammalian SIRT6 Is A Master Regulator Of Glucose Homeostasis

描述（由申请人提供）：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。在缺氧或营养胁迫下，代谢转变为糖酵解，增加乳酸生成并减少线粒体呼吸。这种转换对于维持细胞在饥饿或缺氧期间的生存至关重要；此外，最近的研究表明，在慢性葡萄糖失衡的情况下，如II型糖尿病患者，调节这种开关可能是有益的。染色质是否在碳水化合物流动中起作用尚不清楚。酵母Sir2蛋白是一种nad依赖的组蛋白去乙酰化酶，它感知细胞的代谢状态，并作为染色质沉默者发挥作用，以促进寿命和基因组稳定性。已经发现了7个哺乳动物sirr2同源物（SIRT1-7），但它们的功能尚未完全阐明。最近，我们发现哺乳动物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缺乏会引起严重而致命的低血糖，最终加速死亡。在细胞水平上，SIRT6失活导致细胞葡萄糖摄取增加，乳酸生成增加和线粒体活性降低。初步结果表明，SIRT6是葡萄糖稳态的主要调节剂，调节这些代谢途径中几个关键基因的表达。在这种情况下，SIRT6似乎作为组蛋白H3赖氨酸9 （H3K9）去乙酰化酶起作用，抑制糖酵解基因的表达。本研究的主要目的是测试SIRT6是否在体内调节营养应激，作为染色质调节剂调节参与糖酵解糖代谢向线粒体呼吸转换的多个基因。

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.