SIRT6 protects against pathological damage caused by diet‐induced obesity

Kanfi, Yariv; Peshti, Victoria; Gil, Reuven; Naiman, Shoshana; Nahum, Liat; Levin, Eran; Kronfeld‐Schor, Noga; Cohen, Haim Y.

doi:10.1111/j.1474-9726.2009.00544.x

Cited by 262 publications

(238 citation statements)

References 45 publications

Supporting

Mentioning

224

Contrasting

Order By: Relevance

“…Other members of the sirtuin gene family have been shown to be amenable to pharmacological stimulation (34,35), and recent reports have suggested that SIRT6 may be an intriguing candidate for activation to ameliorate the effect of multiple age-related pathologies. In addition to lifespan extension, a separate study indicated that SIRT6 overexpression protects against diet-induced obesity (36). Additionally, we have observed that SIRT6 overexpression is selectively cytotoxic to multiple cancer cell lines (37), and several studies have suggested that SIRT6 may function as an agonist of NF-κB-induced inflammation (38,39).…”

Section: Discussionmentioning

confidence: 88%

Sirtuin 6 (SIRT6) rescues the decline of homologous recombination repair during replicative senescence

Mao

Tian

Meter

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

160

137

View full text Add to dashboard Cite

Genomic instability is a hallmark of aging tissues. Genomic instability may arise from the inefficient or aberrant function of DNA double-stranded break (DSB) repair. DSBs are repaired by homologous recombination (HR) and nonhomologous DNA end joining (NHEJ). HR is a precise pathway, whereas NHEJ frequently leads to deletions or insertions at the repair site. Here, we used normal human fibroblasts with a chromosomally integrated HR reporter cassette to examine the changes in HR efficiency as cells progress to replicative senescence. We show that HR declines sharply with increasing replicative age, with an up to 38-fold decrease in efficiency in presenescent cells relative to young cells. This decline is not explained by a reduction of the number of cells in S/G 2 /M stage as presenescent cells are actively dividing. Expression of proteins involved in HR such as Rad51, Rad51C, Rad52, NBS1, and Sirtuin 6 (SIRT6) diminished with cellular senescence. Supplementation of Rad51, Rad51C, Rad52, and NBS1 proteins, either individually or in combination, did not rescue the senescence-related decline of HR. However, overexpression of SIRT6 in "middle-aged" and presenescent cells strongly stimulated HR repair, and this effect was dependent on mono-ADP ribosylation activity of poly(ADP-ribose) polymerase (PARP1). These results suggest that in aging cells, the precise HR pathway becomes repressed giving way to a more error-prone NHEJ pathway. These changes in the processing of DSBs may contribute to age-related genomic instability and a higher incidence of cancer with age. SIRT6 activation provides a potential therapeutic strategy to prevent the decline in genome maintenance.A ging is associated with an increased mutation rate (1) and the appearance of genomic rearrangements (2). The accumulation of mutations and rearrangements is a contributing cause of aging and leads to a decline of tissue functionality and an increased incidence of tumors. These mutations and genomic rearrangements arise from aberrant repair of DNA doublestranded breaks (DSBs).DSBs are dangerous DNA lesions. If left unrepaired or repaired incorrectly, DSBs result in a massive loss of genetic information, chromosomal aberrations, or cell death. DSBs are repaired by two major pathways: nonhomologous end joining (NHEJ) and homologous recombination (HR) (3). NHEJ modifies the broken DNA ends and ligates them together with no requirement for homology, often generating deletions or insertions (4). In contrast, HR uses an undamaged DNA template to repair the break, leading to the reconstitution of the original sequence (5). HR repair is responsible for approximately one quarter of DNA repair events and has much slower repair kinetics than NHEJ (6). HR repair begins with the MRE11, NBS1, and Rad50 complex binding to DNA ends and mediating end resection. The RPA protein is then recruited to DNA ends, in a process regulated by CtIP (7). Once the ends are resected, Rad51 forms nucleoprotein filaments and mediates strand invasion of the filament into duplex DNA, usual...

show abstract

Section: Discussionmentioning

confidence: 88%

Sirtuin 6 (SIRT6) rescues the decline of homologous recombination repair during replicative senescence

Mao

Tian

Meter

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

160

137

View full text Add to dashboard Cite

show abstract

“…Mice with a liver-specific deletion of Sirt6 develop a fatty liver, and primary hepatocytes from these mice show relatively low levels of fatty acid oxidation. By contrast, mice with transgenic overexpression of SIRT6 show down-regulation of genes associated with lipid storage and are somewhat protected against the accumulation of visceral fat when placed on a high-fat diet (32). These studies cast Sirt6 as an important promoter of fat utilization.…”

Section: Metabolismmentioning

confidence: 86%

From Sirtuin Biology to Human Diseases: An Update

Sebastián

Satterstrom

Haigis

et al. 2012

Journal of Biological Chemistry

210

159

View full text Add to dashboard Cite

Originally rising to notoriety for their role in the regulation of aging, sirtuins are a family of NAD ؉ -dependent enzymes that have been connected to a steadily growing set of biological processes. In addition to regulating aging, sirtuins play key roles in the maintenance of organismal metabolic homeostasis. These enzymes also have primarily protective functions in the development of many age-related diseases, including cancer, neurodegeneration, and cardiovascular disease. In this minireview, we provide an update on the known roles for each of the seven mammalian sirtuins in these areas.Over three-quarters of a century ago, Clive McCay and colleagues first noted that rats kept on a calorie-restricted diet lived longer than freely fed controls (1). Despite the length of time that has elapsed since this discovery, the molecular mechanism that drives this life span extension has remained elusive. Originally described as a silencing factor in yeast (silencing information regulator), the protein Sir2 came out on top in a screen for modulators of yeast life span (2). Moreover, Sir2 was required for the life span of yeast to be extended by calorie restriction (3). These discoveries launched a new field in biology: the study of Sir2 and its homologs in mammals, called sirtuins.Mammals have seven sirtuins (SIRT1-7) that possess NAD ϩ -dependent deacetylase, deacylase, and ADP-ribosyltransferase activities (4). Sirtuins are found in different subcellular locations, including the nucleus (SIRT1, SIRT6, and SIRT7), cytosol (SIRT2), and mitochondria (SIRT3-5), although in some studies, SIRT1 has been found to possess cytosolic activities, and SIRT2 has been found to associate with nuclear proteins. Sirtuins have important functions in a diverse yet interrelated set of physiological processes. In this minireview, we discuss research done in the past four years featuring their roles in aging, metabolism, cancer biology, cardiovascular disease, inflammation, and brain pathology. AgingFollowing the first publication describing a role for yeast Sir2 in promoting longevity (2), many laboratories focused on elucidating whether sirtuins might play similar roles in other organisms. Sirtuins have been shown to regulate life span in lower organisms, including yeast, nematodes, and fruit flies (5), although their role in worm and fly life span has recently been debated (6, 7). Most of these studies have described a key role for SIRT1 in regulating the metabolic response to calorie restriction (CR) 5 (8), a dietary intervention that robustly extends life span across numerous species. However, wholebody overexpression of SIRT1 in mice does not affect life span (9). Nevertheless, SIRT1 does appear to promote healthy aging by protecting against several age-related pathologies (10).The strongest link between mammalian sirtuins and the antiaging effects of CR comes from SIRT3, which mediates the prevention of age-related hearing loss by CR (11). Hearing loss is a hallmark of mammalian aging and is characterized by a gradual loss of spiral...

show abstract

“…Similarly, Sirt2 does inhibit adipogenesis and accumulation of lipids in 3T3-L1 adipocytes by deacetylation of FOXO1, which represses PPARγ (10). The role of Sirt6 in the regulation of adipogenic differentiation is less clear although it is known that Sirt6 knockout (KO) mice suffer from reduced adipose tissue stores, while Sirt6 overexpressing mice are protected against high-fat diet-induced obesity (11,12). Interestingly, Sirt1 and Sirt6 both mediate effects of rosiglitazone on hepatic lipid accumulation (13).…”

mentioning

confidence: 99%

Sirt7 promotes adipogenesis in the mouse by inhibiting autocatalytic activation of Sirt1

Fang

Ianni

Smolka

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Sirtuins (Sirt1-Sirt7) are NAD + -dependent protein deacetylases/ ADP ribosyltransferases, which play decisive roles in chromatin silencing, cell cycle regulation, cellular differentiation, and metabolism. Different sirtuins control similar cellular processes, suggesting a coordinated mode of action but information about potential cross-regulatory interactions within the sirtuin family is still limited. Here, we demonstrate that Sirt1 requires autodeacetylation to efficiently deacetylate targets such as p53, H3K9, and H4K16. Sirt7 restricts Sirt1 activity by preventing Sirt1 autodeacetylation causing enhanced Sirt1 activity in Sirt7 −/− mice. Increased Sirt1 activity in Sirt7 −/− mice blocks PPARγ and adipocyte differentiation, thereby diminishing accumulation of white fat. Thus, reduction of Sirt1 activity restores adipogenesis in Sirt7 −/− adipocytes in vitro and in vivo. We disclosed a principle controlling Sirt1 activity and uncovered an unexpected complexity in the crosstalk between two different sirtuins. We propose that antagonistic interactions between Sirt1 and Sirt7 are pivotal in controlling the signaling network required for maintenance of adipose tissue.sirtuin | acetylation | adipogenesis T he seven sirtuins in mammals (Sirt1-Sirt7) are involved in the regulation of essential cellular processes. Sirtuins rapidly adjust the activity of chromatin, transcription factors, metabolic enzymes, and structural proteins to cellular needs by deacetylating a broad range of targets. The ability to sense metabolic alterations and various stressors enable sirtuins to adapt cellular homeostasis to varying conditions. It seems likely that this feature of sirtuins is crucial to prevent age-dependent pathologies and promote a healthy lifespan (1, 2).Sirt1 is the most widely studied mammalian sirtuin showing the highest homology to the founding member of the sirtuin family, the yeast silence information regulator, Sir2. Sirt1 deacetylates histones H3K9, H3K56, H4K16, and H1K26 as well as many nonhistone targets thereby contributing to the maintenance of metabolic homeostasis and genomic integrity (3, 4). Sirt1 was also identified as a critical component of lifespan extension in response to calorie restriction in several model organisms, although its exact contribution is still under debate (5). The functions of Sirt7 have attracted less attention compared with Sirt1.

show abstract

SIRT6 protects against pathological damage caused by diet‐induced obesity

Cited by 262 publications

References 45 publications

Sirtuin 6 (SIRT6) rescues the decline of homologous recombination repair during replicative senescence

Sirtuin 6 (SIRT6) rescues the decline of homologous recombination repair during replicative senescence

From Sirtuin Biology to Human Diseases: An Update

Sirt7 promotes adipogenesis in the mouse by inhibiting autocatalytic activation of Sirt1

Contact Info

Product

Resources

About