The Histone Deacetylase Sirt6 Regulates Glucose Homeostasis Via Hif1alpha

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2010 Feb 10

PMID 20141841

Citations 534

Authors

Lei Zhong

Agustina DUrso

Debra Toiber

Carlos Sebastian

Ryan E Henry

Douangsone D Vadysirisack

Alexander Guimaraes

Brett Marinelli

Jakob D Wikstrom

Tomer Nir

Clary B Clish

Bhavapriya Vaitheesvaran

Othon Iliopoulos

Irwin Kurland

Yuval Dor

Ralph Weissleder

Orian S Shirihai

Leif W Ellisen

Joaquin M Espinosa

Raul Mostoslavsky

Affiliations

Soon will be listed here.

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.

Citing Articles

Role of Protein Lysine Acetylation in the Pathogenesis and Treatment of Obesity and Metabolic Syndrome.

Li Z, Song Y, Li Z, Liu S, Yi S, Zhang Z Curr Obes Rep. 2025; 14(1):24.

PMID: 40075037 PMC: 11903573. DOI: 10.1007/s13679-025-00615-1.

Rejuvenation of Bone Marrow Mesenchymal Stem Cells: Mechanisms and Their Application in Senile Osteoporosis Treatment.

Tian R, Zhang R, Ma C Biomolecules. 2025; 15(2).

PMID: 40001580 PMC: 11853522. DOI: 10.3390/biom15020276.

Mitochondria and its epigenetic dynamics: Insight into synaptic regulation and synaptopathies.

Gupta S, Kishore A, Rishi V, Aggarwal A Funct Integr Genomics. 2025; 25(1):26.

PMID: 39849126 DOI: 10.1007/s10142-025-01530-3.

Phylogenetic analysis and detection of positive selection in the SIRT gene family across vertebrates.

Zhou Q, Yang X, Li D, Li J, Peng L, He W Sci Rep. 2025; 15(1):848.

PMID: 39757258 PMC: 11701078. DOI: 10.1038/s41598-025-85344-0.

Sirtuin Proteins and Memory: A Promising Target in Alzheimer's Disease Therapy?.

Fernandez F, Griffiths L, Sutherland H, Cole M, Fitton J, Winberg P Nutrients. 2024; 16(23).

PMID: 39683482 PMC: 11644011. DOI: 10.3390/nu16234088.

References

Milne J, Lambert P, Schenk S, Carney D, Smith J, Gagne D . Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature. 2007; 450(7170):712-6. PMC: 2753457. DOI: 10.1038/nature06261. View

Kilic M, Kasperczyk H, Fulda S, Debatin K . Role of hypoxia inducible factor-1 alpha in modulation of apoptosis resistance. Oncogene. 2006; 26(14):2027-38. DOI: 10.1038/sj.onc.1210008. View

Murray-Rust T, Oldham N, Hewitson K, Schofield C . Purified recombinant hARD1 does not catalyse acetylation of Lys532 of HIF-1alpha fragments in vitro. FEBS Lett. 2006; 580(8):1911-8. DOI: 10.1016/j.febslet.2006.02.012. View

Hirota K, Semenza G . Regulation of hypoxia-inducible factor 1 by prolyl and asparaginyl hydroxylases. Biochem Biophys Res Commun. 2005; 338(1):610-6. DOI: 10.1016/j.bbrc.2005.08.193. View

Baur J, Pearson K, Price N, Jamieson H, Lerin C, Kalra A . Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006; 444(7117):337-42. PMC: 4990206. DOI: 10.1038/nature05354. View

Hu C, Iyer S, Sataur A, Covello K, Chodosh L, Simon M . Differential regulation of the transcriptional activities of hypoxia-inducible factor 1 alpha (HIF-1alpha) and HIF-2alpha in stem cells. Mol Cell Biol. 2006; 26(9):3514-26. PMC: 1447431. DOI: 10.1128/MCB.26.9.3514-3526.2006. View

Arany Z, Huang L, Eckner R, Bhattacharya S, Jiang C, Goldberg M . An essential role for p300/CBP in the cellular response to hypoxia. Proc Natl Acad Sci U S A. 1996; 93(23):12969-73. PMC: 24030. DOI: 10.1073/pnas.93.23.12969. View

Serikawa K, Xu X, MacKay V, Law G, Zong Q, Zhao L . The transcriptome and its translation during recovery from cell cycle arrest in Saccharomyces cerevisiae. Mol Cell Proteomics. 2003; 2(3):191-204. DOI: 10.1074/mcp.D200002-MCP200. View

Kim J, Tchernyshyov I, Semenza G, Dang C . HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 2006; 3(3):177-85. DOI: 10.1016/j.cmet.2006.02.002. View

10.

Zimmer M, Ebert B, Neil C, Brenner K, Papaioannou I, Melas A . Small-molecule inhibitors of HIF-2a translation link its 5'UTR iron-responsive element to oxygen sensing. Mol Cell. 2008; 32(6):838-48. PMC: 3978139. DOI: 10.1016/j.molcel.2008.12.004. View

11.

Liu J, Cao L, Chen J, Song S, Lee I, Quijano C . Bmi1 regulates mitochondrial function and the DNA damage response pathway. Nature. 2009; 459(7245):387-392. PMC: 4721521. DOI: 10.1038/nature08040. View

12.

Mostoslavsky R, Chua K, Lombard D, Pang W, Fischer M, Gellon L . Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell. 2006; 124(2):315-29. DOI: 10.1016/j.cell.2005.11.044. View

13.

Warburg O . On the origin of cancer cells. Science. 1956; 123(3191):309-14. DOI: 10.1126/science.123.3191.309. View

14.

Jeong J, Bae M, Ahn M, Kim S, Sohn T, Bae M . Regulation and destabilization of HIF-1alpha by ARD1-mediated acetylation. Cell. 2002; 111(5):709-20. DOI: 10.1016/s0092-8674(02)01085-1. View

15.

Xu J, Chang V, Joseph S, Trujillo C, Bassilian S, Saad M . Peroxisomal proliferator-activated receptor alpha deficiency diminishes insulin-responsiveness of gluconeogenic/glycolytic/pentose gene expression and substrate cycle flux. Endocrinology. 2003; 145(3):1087-95. DOI: 10.1210/en.2003-1173. View

16.

Arnesen T, Kong X, Evjenth R, Gromyko D, Varhaug J, Lin Z . Interaction between HIF-1 alpha (ODD) and hARD1 does not induce acetylation and destabilization of HIF-1 alpha. FEBS Lett. 2005; 579(28):6428-32. PMC: 4505811. DOI: 10.1016/j.febslet.2005.10.036. View

17.

Bert A, Grepin R, Vadas M, Goodall G . Assessing IRES activity in the HIF-1alpha and other cellular 5' UTRs. RNA. 2006; 12(6):1074-83. PMC: 1464860. DOI: 10.1261/rna.2320506. View

18.

Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F . Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell. 2006; 127(6):1109-22. DOI: 10.1016/j.cell.2006.11.013. View

19.

Chen D, Thomas E, Kapahi P . HIF-1 modulates dietary restriction-mediated lifespan extension via IRE-1 in Caenorhabditis elegans. PLoS Genet. 2009; 5(5):e1000486. PMC: 2676694. DOI: 10.1371/journal.pgen.1000486. View

20.

Xia X, Lemieux M, Li W, Carroll J, Brown M, Liu X . Integrative analysis of HIF binding and transactivation reveals its role in maintaining histone methylation homeostasis. Proc Natl Acad Sci U S A. 2009; 106(11):4260-5. PMC: 2657396. DOI: 10.1073/pnas.0810067106. View