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PMID:20141841
| Citation |
Zhong, L, D'Urso, A, Toiber, D, Sebastian, 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 and Mostoslavsky, R (2010) The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha. Cell 140:280-93 |
|---|---|
| Abstract |
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. |
| Links |
PubMed PMC2821045 Online version:10.1016/j.cell.2009.12.041 |
| Keywords |
Animals; Cell Respiration; Glucose/metabolism; Glucose Transporter Type 1; Glycolysis; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism; Mice; Mice, Knockout; Sirtuins/genetics; Sirtuins/metabolism |
| edit table |
Significance
Annotations
| Gene product | Qualifier | GO Term | Evidence Code | with/from | Aspect | Extension | Notes | Status |
|---|---|---|---|---|---|---|---|---|
| GO:0046325: negative regulation of glucose import |
ECO:0000315: |
P |
Figure 1 shows Increased glucose uptake in SIRT6 deficient cells and mice |
complete | ||||
| GO:0045820: negative regulation of glycolysis |
ECO:0000315: |
P |
Figure 2C displays significantly higher levels of lactate in SIRT6 deficient cells when compared to WT |
complete | ||||
| GO:0046969: NAD-dependent histone deacetylase activity (H3-K9 specific) |
ECO:0000315: |
F |
Figure 3 shows SIRT6 directly inhibits expression of glycolytic genes functioning as an H3K9 deacetylase |
complete | ||||
| GO:0045892: negative regulation of transcription, DNA-dependent |
ECO:0000315: |
P |
Fig 4 |
complete | ||||
| GO:0031648: protein destabilization |
ECO:0000315: |
P |
Figure 6 |
complete | ||||
|
enables |
GO:0046969: NAD-dependent histone deacetylase activity (H3-K9 specific) |
ECO:0000315: mutant phenotype evidence used in manual assertion |
F |
Seeded From UniProt |
complete | |||
|
involved_in |
GO:0045892: negative regulation of transcription, DNA-templated |
ECO:0000315: mutant phenotype evidence used in manual assertion |
P |
Seeded From UniProt |
complete | |||
|
involved_in |
GO:0046325: negative regulation of glucose import |
ECO:0000315: mutant phenotype evidence used in manual assertion |
P |
Seeded From UniProt |
complete | |||
|
involved_in |
GO:0031648: protein destabilization |
ECO:0000315: mutant phenotype evidence used in manual assertion |
P |
Seeded From UniProt |
complete | |||
|
involved_in |
GO:0045820: negative regulation of glycolytic process |
ECO:0000315: mutant phenotype evidence used in manual assertion |
P |
Seeded From UniProt |
complete | |||
See also
References
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