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.
Zhong
Lei
L
The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
D'Urso
Agustina
A
Toiber
Debra
D
Sebastian
Carlos
C
Henry
Ryan E
RE
Vadysirisack
Douangsone D
DD
Guimaraes
Alexander
A
Marinelli
Brett
B
Wikstrom
Jakob D
JD
Nir
Tomer
T
Clish
Clary B
CB
Vaitheesvaran
Bhavapriya
B
Iliopoulos
Othon
O
Kurland
Irwin
I
Dor
Yuval
Y
Weissleder
Ralph
R
Shirihai
Orian S
OS
Ellisen
Leif W
LW
Espinosa
Joaquin M
JM
Mostoslavsky
Raul
R
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