The Histone Deacetylase Sirt6 Regulates Glucose Homeostasis via Hif1α

Lei Zhong, Agustina D'Urso, 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 J. Kurland, Yuval Dor, Ralph Weissleder, Orian S. Shirihai, Leif W. Ellisen, Joaquin M. Espinosa, Raul Mostoslavsky

Research output: Contribution to journalArticle

555 Citations (Scopus)

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 Hif1α, a critical regulator of nutrient stress responses. Consistent with this notion, SIRT6-deficient cells exhibit increased Hif1α 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.

Original languageEnglish (US)
Pages (from-to)280-293
Number of pages14
JournalCell
Volume140
Issue number2
DOIs
StatePublished - Jan 22 2010

Fingerprint

Histone Deacetylases
Hypoglycemia
Homeostasis
Glucose
Co-Repressor Proteins
Metabolic Diseases
Glycolysis
Medical problems
Psychological Stress
Metabolism
NAD
Nutrients
Chromatin
Respiration
Transcription Factors
Up-Regulation
Obesity
Genes
Food
Therapeutics

Keywords

  • CELLBIO
  • HUMDISEASE
  • RNA

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Zhong, L., D'Urso, A., Toiber, D., Sebastian, C., Henry, R. E., Vadysirisack, D. D., ... Mostoslavsky, R. (2010). The Histone Deacetylase Sirt6 Regulates Glucose Homeostasis via Hif1α. Cell, 140(2), 280-293. https://doi.org/10.1016/j.cell.2009.12.041

The Histone Deacetylase Sirt6 Regulates Glucose Homeostasis via Hif1α. / Zhong, Lei; D'Urso, Agustina; Toiber, Debra; Sebastian, Carlos; Henry, Ryan E.; Vadysirisack, Douangsone D.; Guimaraes, Alexander; Marinelli, Brett; Wikstrom, Jakob D.; Nir, Tomer; Clish, Clary B.; Vaitheesvaran, Bhavapriya; Iliopoulos, Othon; Kurland, Irwin J.; Dor, Yuval; Weissleder, Ralph; Shirihai, Orian S.; Ellisen, Leif W.; Espinosa, Joaquin M.; Mostoslavsky, Raul.

In: Cell, Vol. 140, No. 2, 22.01.2010, p. 280-293.

Research output: Contribution to journalArticle

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, IJ, Dor, Y, Weissleder, R, Shirihai, OS, Ellisen, LW, Espinosa, JM & Mostoslavsky, R 2010, 'The Histone Deacetylase Sirt6 Regulates Glucose Homeostasis via Hif1α', Cell, vol. 140, no. 2, pp. 280-293. https://doi.org/10.1016/j.cell.2009.12.041
Zhong L, D'Urso A, Toiber D, Sebastian C, Henry RE, Vadysirisack DD et al. The Histone Deacetylase Sirt6 Regulates Glucose Homeostasis via Hif1α. Cell. 2010 Jan 22;140(2):280-293. https://doi.org/10.1016/j.cell.2009.12.041
Zhong, Lei ; D'Urso, Agustina ; Toiber, Debra ; Sebastian, Carlos ; Henry, Ryan E. ; Vadysirisack, Douangsone D. ; Guimaraes, Alexander ; Marinelli, Brett ; Wikstrom, Jakob D. ; Nir, Tomer ; Clish, Clary B. ; Vaitheesvaran, Bhavapriya ; Iliopoulos, Othon ; Kurland, Irwin J. ; Dor, Yuval ; Weissleder, Ralph ; Shirihai, Orian S. ; Ellisen, Leif W. ; Espinosa, Joaquin M. ; Mostoslavsky, Raul. / The Histone Deacetylase Sirt6 Regulates Glucose Homeostasis via Hif1α. In: Cell. 2010 ; Vol. 140, No. 2. pp. 280-293.
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