Author/Authors :
Lei Zhong، نويسنده , , Agustina DʹUrso، نويسنده , , Debra Toiber، نويسنده , , Carlos Sebastian، نويسنده , , Ryan E. Henry، نويسنده , , Douangsone D. Vadysirisack، نويسنده , , Alexander Guimaraes، نويسنده , , Brett Marinelli، نويسنده , , Jakob D. Wikstrom، نويسنده , , Tomer Nir، نويسنده , , Clary B. Clish، نويسنده , , Bhavapriya Vaitheesvaran، نويسنده , , Othon Iliopoulos، نويسنده , , Irwin Kurland، نويسنده , , Yuval Dor، نويسنده , , Ralph Weissleder، نويسنده , , Orian S. Shirihai، نويسنده , , Leif W. Ellisen، نويسنده , , Joaquin M. Espinosa، نويسنده , , Raul Mostoslavsky، نويسنده , , et al.، نويسنده ,
Abstract :
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 Hif1α, a critical regulator of nutrient stress responses. Consistent with this notion, SIRT6-deficient cells exhibit increased Hif1α 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.
