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Cell. 2010 Jan 22;140(2):280-93. doi: 10.1016/j.cell.2009.12.041.

The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha.

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  • 1The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.

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.

Copyright 2010 Elsevier Inc. All rights reserved.

PMID:
20141841
[PubMed - indexed for MEDLINE]
PMCID:
PMC2821045
Free PMC Article

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