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 Kurland; Yuval Dor; Ralph Weissleder; Orian S. Shirihai; Leif W. Ellisen; Joaquin M. Espinosa; Raul Mostoslavsky

doi:10.1016/j.cell.2009.12.041

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 Kurland, Yuval Dor, Ralph Weissleder, Orian S. Shirihai, Leif W. Ellisen, Joaquin M. Espinosa, Raul Mostoslavsky

Research output: Contribution to journal › Article › peer-review

874 Scopus citations

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 language	English
Pages (from-to)	280-293
Number of pages	14
Journal	Cell
Volume	140
Issue number	2
DOIs	https://doi.org/10.1016/j.cell.2009.12.041
State	Published - 22 Jan 2010
Externally published	Yes

Keywords

CELLBIO
HUMDISEASE
RNA

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.cell.2009.12.041

Cite this

Zhong, L., D'Urso, A., Toiber, D., Sebastian, C., Henry, R. E., Vadysirisack, D. D., Guimaraes, A., Marinelli, B., Wikstrom, J. D., Nir, T., Clish, C. B., Vaitheesvaran, B., Iliopoulos, O., Kurland, I., Dor, Y., Weissleder, R., Shirihai, O. S., Ellisen, L. W., Espinosa, J. M., & 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

@article{c0e4dfd8da3f417db6749f8b9e5f682e,

title = "The Histone Deacetylase Sirt6 Regulates Glucose Homeostasis via Hif1α",

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.",

keywords = "CELLBIO, HUMDISEASE, RNA",

author = "Lei Zhong and Agustina D'Urso and Debra Toiber and Carlos Sebastian and Henry, {Ryan E.} and Vadysirisack, {Douangsone D.} and Alexander Guimaraes and Brett Marinelli and Wikstrom, {Jakob D.} and Tomer Nir and Clish, {Clary B.} and Bhavapriya Vaitheesvaran and Othon Iliopoulos and Irwin Kurland and Yuval Dor and Ralph Weissleder and Shirihai, {Orian S.} and Ellisen, {Leif W.} and Espinosa, {Joaquin M.} and Raul Mostoslavsky",

note = "Funding Information: This work was supported by the V Foundation (R.M.), the Sidney Kimmel Cancer Research Foundation (R.M.), a New Investigator Grant from AFAR (R.M.), A New Investigator Award from The Massachusetts Life Sciences Center (R.M.), a P&F Award from the Joslin Diabetes Center (R.M.), and Grant P30 DK57521 from the Metabolic Physiology Core (BADERC). D.T. is supported by a fellowship from the Brain Power for Israel Fund. Y.D. is supported by JDRF. J.M.E. is supported by NIH-RO1 CA117907 and the Howard Hughes Medical Institute. We thank Magali Silberman, Daniel Holoch, Pere Puigserver, John Dominy, Matthew Vander Heiden, Mike Zimmer, David Lombard, Bjoern Schwer, Fred Alt, Katrin Chua, and members of the Bardeesy, Hochedlinger, Hock, and Ramaswamy labs for reagents and helpful discussions. We thank Kelly Shay, Laura Prickett-Rice, and Kate Folz-Donahue for technical assistance. We are also thankful to Nabeel Bardeesy and Hanno Hock for critically reading the manuscript and Jose Polo for assistance with the ChIP assays. ",

year = "2010",

month = jan,

day = "22",

doi = "10.1016/j.cell.2009.12.041",

language = "English",

volume = "140",

pages = "280--293",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier B.V.",

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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 & 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

TY - JOUR

T1 - The Histone Deacetylase Sirt6 Regulates Glucose Homeostasis via Hif1α

AU - Zhong, Lei

AU - D'Urso, Agustina

AU - Toiber, Debra

AU - Sebastian, Carlos

AU - Henry, Ryan E.

AU - Vadysirisack, Douangsone D.

AU - Guimaraes, Alexander

AU - Marinelli, Brett

AU - Wikstrom, Jakob D.

AU - Nir, Tomer

AU - Clish, Clary B.

AU - Vaitheesvaran, Bhavapriya

AU - Iliopoulos, Othon

AU - Kurland, Irwin

AU - Dor, Yuval

AU - Weissleder, Ralph

AU - Shirihai, Orian S.

AU - Ellisen, Leif W.

AU - Espinosa, Joaquin M.

AU - Mostoslavsky, Raul

N1 - Funding Information: This work was supported by the V Foundation (R.M.), the Sidney Kimmel Cancer Research Foundation (R.M.), a New Investigator Grant from AFAR (R.M.), A New Investigator Award from The Massachusetts Life Sciences Center (R.M.), a P&F Award from the Joslin Diabetes Center (R.M.), and Grant P30 DK57521 from the Metabolic Physiology Core (BADERC). D.T. is supported by a fellowship from the Brain Power for Israel Fund. Y.D. is supported by JDRF. J.M.E. is supported by NIH-RO1 CA117907 and the Howard Hughes Medical Institute. We thank Magali Silberman, Daniel Holoch, Pere Puigserver, John Dominy, Matthew Vander Heiden, Mike Zimmer, David Lombard, Bjoern Schwer, Fred Alt, Katrin Chua, and members of the Bardeesy, Hochedlinger, Hock, and Ramaswamy labs for reagents and helpful discussions. We thank Kelly Shay, Laura Prickett-Rice, and Kate Folz-Donahue for technical assistance. We are also thankful to Nabeel Bardeesy and Hanno Hock for critically reading the manuscript and Jose Polo for assistance with the ChIP assays.

PY - 2010/1/22

Y1 - 2010/1/22

N2 - 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.

AB - 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.

KW - CELLBIO

KW - HUMDISEASE

KW - RNA

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U2 - 10.1016/j.cell.2009.12.041

DO - 10.1016/j.cell.2009.12.041

M3 - Article

C2 - 20141841

AN - SCOPUS:74549142287

SN - 0092-8674

VL - 140

SP - 280

EP - 293

JO - Cell

JF - Cell

IS - 2

ER -

The Histone Deacetylase Sirt6 Regulates Glucose Homeostasis via Hif1α

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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