The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
Cell. 2010 Jan 22;140(2):280-93. doi: 10.1016/j.cell.2009.12.041.
SIRT6 is a member of a highly conserved family of NAD(+)-dependent deacetylases with various roles in metabolism, stress resistance, and life span. SIRT6-deficient mice develop normally but succumb to a lethal hypoglycemia early in life; however, the mechanism underlying this hypoglycemia remained unclear. Here, we demonstrate that SIRT6 functions as a histone H3K9 deacetylase to control the expression of multiple glycolytic genes. Specifically, SIRT6 appears to function as a corepressor of the transcription factor Hif1alpha, a critical regulator of nutrient stress responses. Consistent with this notion, SIRT6-deficient cells exhibit increased Hif1alpha activity and show increased glucose uptake with upregulation of glycolysis and diminished mitochondrial respiration. Our studies uncover a role for the chromatin factor SIRT6 as a master regulator of glucose homeostasis and may provide the basis for novel therapeutic approaches against metabolic diseases, such as diabetes and obesity.
SIRT6 是一种高度保守的 NAD（+）依赖去乙酰化酶家族的成员，在代谢、应激抵抗和寿命方面具有多种作用。SIRT6 缺陷型小鼠正常发育，但在生命早期会遭受致命性低血糖的影响；然而，导致这种低血糖的机制仍不清楚。在这里，我们证明 SIRT6 作为组蛋白 H3K9 去乙酰化酶发挥作用，以控制多种糖酵解基因的表达。具体来说，SIRT6 似乎作为转录因子 Hif1alpha 的核心抑制因子发挥作用，Hif1alpha 是营养应激反应的关键调节剂。与这一观点一致的是，SIRT6 缺陷型细胞表现出 Hif1alpha 活性增加，并表现出葡萄糖摄取增加，糖酵解上调，线粒体呼吸减少。我们的研究揭示了染色质因子 SIRT6 作为葡萄糖稳态的主调控因子的作用，可能为治疗代谢性疾病（如糖尿病和肥胖症）提供新的治疗方法的基础。
