The Histone Deacetylase Sirt6 Regulates Glucose Homeostasis via Hif1α

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 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.

DOI: 10.1016/j.cell.2009.12.041

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@article{Zhong2010TheHD, title={The Histone Deacetylase Sirt6 Regulates Glucose Homeostasis via Hif1α}, author={Lei Zhong and Agustina D'Urso and Debra Toiber and Carlos Sebasti{\'a}n and Ryan Henry and Douangsone D. Vadysirisack and A Guimaraes and Brett S Marinelli and Jakob D Wikstrom and Tomer Nir and Clary B Clish and Bhavapriya Vaitheesvaran and Othon Iliopoulos and Irwin Jack Kurland and Yuval Dor and Ralph Weissleder and Orian S Shirihai and Leif William Ellisen and Joaqu{\'i}n M Espinosa and Raul Mostoslavsky}, journal={Cell}, year={2010}, volume={140}, pages={280-293} }