The histone deacetylase SIRT6 functions as a co-repressor of Hif1 alpha in glucos

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，代谢转换为糖酵解，通过涉及转录因子Hif11的机制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可以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似乎在染色质上起作用，以减弱Hif11转录的营养反应。SIRT6结合Hif11，作为组蛋白H3赖氨酸9 （H3K9）去乙酰化酶抑制Hif11靶基因启动子的表达。本研究的主要目的是明确测试SIRT6是否调节营养应激，作为染色质修饰剂调节参与糖酵解和线粒体呼吸转换葡萄糖代谢的多个基因。

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 through a mechanism that involves the transcription factor Hif11. 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 can regulate expression of several key genes in these metabolic pathways. In this context, SIRT6 appears to function at chromatin to attenuate a Hif11 transcriptional nutrient response. SIRT6 binds to Hif11 and acts as a histone H3 lysine9 (H3K9) deacetylase to inhibit expression of Hif11-target gene promoters. The main goal of this proposal is to test specifically whether SIRT6 regulates nutrient stress, functioning as a chromatin modifier to modulate multiple genes involved in switching glucose metabolism away of glycolysis and towards mitochondrial respiration.