Cell
Volume 140, Issue 2, 22 January 2010, Pages 280-293
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Article
The Histone Deacetylase Sirt6 Regulates Glucose Homeostasis via Hif1α

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Summary

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.

Highlights

► 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

CELLBIO
HUMDISEASE
RNA

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