The Histone Deacetylase Sirt6 Regulates Glucose Homeostasis via Hif1α

Abstract

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.

Epigenetic regulation of aging stem cells

“…Understanding the role of Sirtuins in aging stem cells will likely provide insights into the mechanisms that regulate stem cell homeostasis, particularly in response to stress stimuli. In addition, the ability of Sirtuins to regulate both organismal energy metabolism (Banks et al, 2008;Feige et al, 2008;Kim et al, 2010;Ramadori et al, 2010;Zhong et al, 2010) and chromatin may be particularly important for the response of adult stem cells to environmental stimuli such as dietary restriction that are known to promote longevity and delay signs of aging.…”

Do Sirtuins Promote Mammalian Longevity?: A Critical Review on Its Relevance to the Longevity Effect Induced by Calorie Restriction

“…SIRT3, 4, and 5 regulate ATP production, metabolism, apoptosis, and cell signaling (Haigis et al, 2006;Michishita et al, 2005;Onyango et al, 2002;Schwer et al, 2002). SIRT6 is involved in genomic DNA stability and repair, and crucial in metabolism and aging Zhong et al, 2010). No robust activity has been found for SIRT7 as of yet (Table 1).…”

“…SIRT6 is likely linked to cellular metabolism and aging. A study of mice with a targeted deletion of SIRT6 showed that SIRT6 is essential for survival and controls glucose homeostasis through HIF-1α (Mostosalvsky et al, 2006;Zhong et al, 2010). SIRT6 interacts with NF-κB and deacetylates histone H3 lysine 9 (H3K9) at NF-κB target gene promoters leading to inactivation of many of the same transcriptional programs observed in aged tissues, including genes controlled by NF-κB (Kawahara et al, 2009).…”

Comparative study of the promotion of porcine fetal fibroblast proliferation by overexpression of two transcriptional variants of SIRT6

“…As a mono-ADP-ribosyltransferase, SIRT6 uses NAD + as a cosubstrate to transfer the 32 P-label from NAD + to mSIRT6 and histones [4-6]. SIRT6 harbors low-level deacetylase activity for NAD + -dependent deacetylation of non-histone proteins [7] and linking site-specific histones [8][9][10][11].SIRT6 is present in all eukaryotes including mammals [12], and deacetylates histone H3 lysine 9 (H3K9) and histone H3 lysine K56 (H3K56) to maintain dynamic changes in their acetylation levels at the telomeres over cell cycles. Histone deacetylation modifies the telomeric chromatin by preventing chromosomal fusion at the end of telomeres, and negatively regulates ageing-correlated gene-expression programs depending on nuclear factor-B [8,9,13].…”

“…As a mono-ADP-ribosyltransferase, SIRT6 uses NAD + as a cosubstrate to transfer the 32 P-label from NAD + to mSIRT6 and histones [4-6]. SIRT6 harbors low-level deacetylase activity for NAD + -dependent deacetylation of non-histone proteins [7] and linking site-specific histones [8][9][10][11].…”