The Histone Deacetylase SIRT6 Regulates Glucose Homeostasis via Hif1α

By Lei Zhong, Agustina D’Urso, D. Toiber, C. Sebastián, R. Henry, D. Vadysirisack, Alexander R. Guimaraes, Brett Marinelli, J. Wikstrom, T. Nir and 10 more. Cell, 2010

993 citations recorded by the source corpus.

Summary SIRT6 is a member of a highly conserved family of NAD+-dependent deacetylases with various roles in metabolism, stress resistance and lifespan. 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 co-repressor 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 up-regulation of glycolysis and diminished mitochondrial respiration. Our studies uncover a novel 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.

Subfields: Epidemiology, Geriatrics and Gerontology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/94337271fe9fb0c327c0ce06e683cac6a8888b66

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Epidemiology

In Geriatrics and Gerontology

In Molecular Biology

Citations in the corpus

Transcriptional Regulation by Hypoxia Inducible Factors (2013, background): “However, several other groups have failed to detect acetylation of Lys-532, even in the same cell lines (Arnesen et al., 2005; Murray-Rust et al., 2006; Zhong et al., 2010).”
Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1alpha. (2010, background): “Indeed, this idea is supported by a recent report which showed that a sirtuin member regulates glucose homeostasis via HIF-1a, more specifically, SIRT6 was found to downregulate glycolytic enzymes by binding and inactivating HIF-1a (Zhong et al., 2010).”
THE HISTONE DEACETYLASE SIRT6 IS A NOVEL TUMOR SUPPRESSOR THAT CONTROLS CANCER METABOLISM (2012, positive): “MYC has been described as a transcriptional activator of genes involved in ribosome biogenesis (van Riggelen et al., 2010), whereas we and others have described a role for SIRT6 as a transcriptional repressor (Kawahara et al., 2009; Zhong et al., 2010).”
Sirtuins as regulators of metabolism and healthspan (2012, background): “18 ) were reported to function as ADP-ribosyltransferases , even though SIRT6 also can act as a deacetylas”
SIRT1 and other sirtuins in Metabolism (2013, background): “N IH -PA Author M anuscript N IH -PA Author M anuscript N IH -PA Author M anuscript hypoxia-inducible factor 1α (HIF-1α) [60].”
miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling (2011, background): “We identify herein six miR-33 target genes that regulate fatty acid metabolism and insulin signaling, including CPT1a, CROT, HADHB, AMPKα, SIRT6, and IRS2.”
Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging (2013, background): “Interestingly, SIRT1 increases HIF-1a transcriptional activity (Lim et al., 2010), SIRT3 destabilizes HIF-1a protein (Bell et al., 2011; Finley et al., 2011), and SIRT6 functions as a HIF-1a corepressor (Zhong et al., 2010), raising the possibility that HIF-1amay also be relevant to aging.”
The hallmarks of aging. (2013, background): “More compelling evidence for a sirtuin-mediated prolongevity role in mammals has been obtained for SIRT6, which regulates genomic stability, NF-kB signaling, and glucose homeostasis through histone H3K9 deacetylation (Kanfi et al., 2010; Kawahara et al., 2009; Zhong et al., 2010).”
NAD+ metabolism and the control of energy homeostasis - a balancing act between mitochondria and the nucleus (2015, background): “…age-related disease or reduced maximal lifespan (Boutant and Canto, 2014; Hirschey et al., 2011; Ryu et al., 2014; Vakhrusheva et al., 2008), while the absence of SIRT6 causes severe hypoglycemia, leading to mortality within the first month of life (Mostoslavsky et al., 2006; Zhong et al., 2010).”
The Role of the Reactive Oxygen Species and Oxidative Stress in the Pathomechanism of the Age-Related Ocular Diseases and Other Pathologies of the Anterior and Posterior Eye Segments in Adults (2016, background): “Sirt6 is a nuclear chromatin-bound protein, which regulates glucose homeostasis [158], has antiaging and anti-inflammatory properties, and is involved in the oxidative stress-induced endothelial cells senescence pathomechanism [159, 160].”