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The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha. 2010
Lei Zhong, and
Agustina D'Urso, and
Debra Toiber, and
Carlos Sebastian, and
Ryan E Henry, and
Douangsone D Vadysirisack, and
Alexander Guimaraes, and
Brett Marinelli, and
Jakob D Wikstrom, and
Tomer Nir, and
Clary B Clish, and
Bhavapriya Vaitheesvaran, and
Othon Iliopoulos, and
Irwin Kurland, and
Yuval Dor, and
Ralph Weissleder, and
Orian S Shirihai, and
Leif W Ellisen, and
Joaquin M Espinosa, and
Raul Mostoslavsky
The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
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.
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Othon Iliopoulos, and
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Ralph Weissleder, and
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Brett Marinelli, and
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Clary B Clish, and
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Bhavapriya Vaitheesvaran, and
Othon Iliopoulos, and
Irwin Kurland, and
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