The Histone Deacetylase Sirt6 Regulates Glucose Homeostasis via Hif1α

• Published in: Cell 2010-01, Vol.140 (2), p.280-293
• Main Authors: Zhong, Lei, D'Urso, Agustina, Toiber, Debra, Sebastian, Carlos, Henry, Ryan E., Vadysirisack, Douangsone D., Guimaraes, Alexander, Marinelli, Brett, Wikstrom, Jakob D., Nir, Tomer, Clish, Clary B., Vaitheesvaran, Bhavapriya, Iliopoulos, Othon, Kurland, Irwin, Dor, Yuval, Weissleder, Ralph, Shirihai, Orian S., Ellisen, Leif W., Espinosa, Joaquin M., Mostoslavsky, Raul
• Format: Article
• Language: English
• Subjects: CELLBIO; HUMDISEASE; NATURAL SCIENCES; NATURVETENSKAP; RNA
• ISSN: 0092-8674; 1097-4172; 1097-4172
• 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 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. [Display omitted] ► SIRT6 acts as a histone deacetylase to directly repress multiple glycolytic genes ► SIRT6 also functions as a corepressor of the transcription factor Hif1α ► Loss of SIRT6 increases glycolysis and diminishes mitochondrial respiration ► SIRT6 plays a key role in regulating glucose homeostasis