The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha.
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.
|Year of Publication||
2010 Jan 22
|PubMed Central ID||
R01 DK035914 / DK / NIDDK NIH HHS / United States
R01 GM093072 / GM / NIGMS NIH HHS / United States
R01 CA117907 / CA / NCI NIH HHS / United States
Howard Hughes Medical Institute / United States
R01 CA122589 / CA / NCI NIH HHS / United States
P30 DK57521 / DK / NIDDK NIH HHS / United States
P30 DK057521 / DK / NIDDK NIH HHS / United States
R01 DK056690 / DK / NIDDK NIH HHS / United States
R01 CA117907-01 / CA / NCI NIH HHS / United States
R01 DK058132-10 / DK / NIDDK NIH HHS / United States
R01 DK088190 / DK / NIDDK NIH HHS / United States