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

描述（由申请人提供）：有效的葡萄糖代谢对于维持细胞活力至关重要。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。在缺氧或营养应激下，新陈代谢转变为糖酵解，通过涉及转录因子 Hif11 的机制增加乳酸产量并减少线粒体呼吸。这种转换对于在饥饿或缺氧期间维持细胞至关重要。此外，最近的研究表明，在慢性葡萄糖失衡的情况下，例如 II 型糖尿病患者，调节这种开关可能是有益的。目前尚不清楚染色质是否在碳水化合物流动中发挥作用。酵母 Sir2 蛋白是一种 NAD 依赖性组蛋白脱乙酰酶，可感知细胞的代谢状态，并作为染色质沉默子发挥作用，以促进寿命和基因组稳定性。已发现 7 个哺乳动物 Sir2 同源物 (SIRT1-7)，但其功能仍有待充分阐明。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 缺陷会引发严重且致命的低血糖，最终导致加速死亡。在细胞水平上，SIRT6 失活会导致细胞葡萄糖摄取增加、乳酸产量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 似乎在染色质上发挥作用，减弱 Hif11 转录营养反应。 SIRT6 与 Hif11 结合并充当组蛋白 H3 赖氨酸 9 (H3K9) 脱乙酰酶来抑制 Hif11 靶基因启动子的表达。该提案的主要目标是专门测试 SIRT6 是否调节营养应激，作为染色质修饰剂来调节涉及将葡萄糖代谢从糖酵解转向线粒体呼吸的多个基因。

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.