Tier 3 — preclinical

The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha

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
Cell 2010 140(2):280-293

Bibliography

PubMed
PMID 20141841
PubMed Central
PMC2821045
DOI
10.1016/j.cell.2009.12.041
Funding
Supported by the V Foundation, Sidney Kimmel Cancer Research Foundation, an AFAR New Investigator Grant, Metabolic Physiology Core grant P30 DK57521, JDRF support, NIH R01 CA117907, and the Howard Hughes Medical Institute.
Competing interests
No competing-interest statement was identified in the accessible full-text record.

Study snapshot

DesignMechanistic metabolic study of SIRT6 control of HIF-1alpha and glycolytic gene expression.
ModelSIRT6-deficient mice and cultured cells.
SamplePreclinical experiments; assay-specific sample sizes reported in the paper.
InterventionGenetic SIRT6 deficiency and HIF-1alpha pathway manipulation.
DurationExperiment-dependent.
EndpointsGlucose uptake; glycolysis; mitochondrial respiration; HIF-1alpha activity; H3K9 deacetylation at glycolytic genes

What the study showed, in plain terms

This study established SIRT6 as a major regulator of glucose metabolism. Loss of SIRT6 increased HIF-1alpha activity, glucose uptake and glycolysis while reducing mitochondrial respiration.

Key findings

SIRT6 acts as a chromatin corepressor of HIF-1alpha-dependent glycolytic genes and is required for normal glucose homeostasis in the studied models.

What this study can and cannot tell us

The evidence is genetic and preclinical; it does not establish that pharmacologically activating SIRT6 improves diabetes, obesity or glucose control in humans.

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Dr. Khaled Mahmoud, MBBChCritical Care Medicine, Longevity Science & Editorial Direction Dr. Abdulla Mostafa, PhDCellular Senescence, Neurological, Mitochondrial & Brain-Ageing Biology Dr. Amr Yasser, PhDCardiometabolic, Musculoskeletal, Gut & Bioavailability