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Cell DOI:10.1016/j.cell.2009.12.041

The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha.

Publication TypeJournal Article
Year of Publication2010
AuthorsZhong, L, D'Urso, A, Toiber, D, Sebastián, C, Henry, RE, Vadysirisack, DD, Guimaraes, A, Marinelli, B, Wikstrom, JD, Nir, T, Clish, CB, Vaitheesvaran, B, Iliopoulos, O, Kurland, I, Dor, Y, Weissleder, R, Shirihai, OS, Ellisen, LW, Espinosa, JM, Mostoslavsky, R
Date Published2010 Jan 22
KeywordsAnimals, Cell Respiration, Glucose, Glucose Transporter Type 1, Glycolysis, Hypoxia-Inducible Factor 1, alpha Subunit, Mice, Mice, Knockout, Sirtuins

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.


Alternate JournalCell
PubMed ID20141841
PubMed Central IDPMC2821045
Grant ListR01 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