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.
The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
Lei
L
Zhong
Agustina
A
D'Urso
Debra
D
Toiber
Carlos
C
Sebastian
Ryan E
RE
Henry
Douangsone D
DD
Vadysirisack
Alexander
A
Guimaraes
Brett
B
Marinelli
Jakob D
JD
Wikstrom
Tomer
T
Nir
Clary B
CB
Clish
Bhavapriya
B
Vaitheesvaran
Othon
O
Iliopoulos
Irwin
I
Kurland
Yuval
Y
Dor
Ralph
R
Weissleder
Orian S
OS
Shirihai
Leif W
LW
Ellisen
Joaquin M
JM
Espinosa
Raul
R
Mostoslavsky
D000818:Animals; D019069:Cell Respiration; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1; D006019:Glycolysis; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*
D051272:Glucose Transporter Type 1; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C495678:Slc2a1 protein, mouse; C501860:Sirt6 protein, mouse; D037761:Sirtuins; D005947:Glucose