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• W2056564149 abstract "•Sirtuins respond to energy level changes and execute salutary effects resembling calorie restriction (CR)•Sirtuins mediate CR effects in various cellular compartments and are crucial metabolic regulators in multiple tissues.•Small molecules that enhance sirtuin activities, including CR mimetics and NAD+ precursors, are promising strategies to ameliorate age-related diseases. Sirtuins such as SIRT1 are conserved protein NAD+-dependent deacylases and thus their function is intrinsically linked to cellular metabolism. Over the past two decades, accumulating evidence has indicated that sirtuins are not only important energy status sensors but also protect cells against metabolic stresses. Sirtuins regulate the aging process and are themselves regulated by diet and environmental stress. The versatile functions of sirtuins including, more specifically, SIRT1 are supported by their diverse cellular location allowing cells to sense changes in energy levels in the nucleus, cytoplasm, and mitochondrion. SIRT1 plays a critical role in metabolic health by deacetylating many target proteins in numerous tissues, including liver, muscle, adipose tissue, heart, and endothelium. This sirtuin also exerts important systemic effects via the hypothalamus. This review will cover these topics and suggest that strategies to maintain sirtuin activity may be on the horizon to forestall diseases of aging. Sirtuins such as SIRT1 are conserved protein NAD+-dependent deacylases and thus their function is intrinsically linked to cellular metabolism. Over the past two decades, accumulating evidence has indicated that sirtuins are not only important energy status sensors but also protect cells against metabolic stresses. Sirtuins regulate the aging process and are themselves regulated by diet and environmental stress. The versatile functions of sirtuins including, more specifically, SIRT1 are supported by their diverse cellular location allowing cells to sense changes in energy levels in the nucleus, cytoplasm, and mitochondrion. SIRT1 plays a critical role in metabolic health by deacetylating many target proteins in numerous tissues, including liver, muscle, adipose tissue, heart, and endothelium. This sirtuin also exerts important systemic effects via the hypothalamus. This review will cover these topics and suggest that strategies to maintain sirtuin activity may be on the horizon to forestall diseases of aging. Sirtuins: indispensable energy sensorsSirtuins are class III histone deacylases that consume one molecule of NAD+ (see Glossary) during each deacylation cycle [1Imai S. et al.Transcriptional silencing and longevity protein sir2 is an NAD-dependent histone deacetylase.Nature. 2000; 403: 795-800Crossref PubMed Scopus (1470) Google Scholar]. The first identified sirtuin protein was silent information regulator 2 (SIR2) from Saccharomyces cerevisiae. SIR2 was originally characterized as a chromatin-silencing component that repressed gene transcription at selected loci [2Klar A.J. et al.Mar1-a regulator of the hma and hmalpha loci in Saccharomyces cerevisiae.Genetics. 1979; 93: 37-50Crossref PubMed Google Scholar]. Soon after the discovery that SIR2 extended the replicative lifespan of yeast [3Sinclair D.A. Guarente L. Extrachromosomal rdna circles--a cause of aging in yeast.Cell. 1997; 91: 1033-1042Abstract Full Text Full Text PDF PubMed Scopus (702) Google Scholar, 4Kaeberlein M. et al.The sir2/3/4 complex and sir2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms.Genes Dev. 1999; 13: 2570-2580Crossref PubMed Scopus (963) Google Scholar], the orthologs of SIR2 were proposed to carry out the same lifespan-prolonging effects in Caenorhabditis elegans [5Tissenbaum H.A. Guarente L. Increased dosage of a sir-2 gene extends lifespan in caenorhabditis elegans.Nature. 2001; 410: 227-230Crossref PubMed Scopus (1026) Google Scholar, 6Viswanathan M. Guarente L. Regulation of caenorhabditis elegans lifespan by sir-2.1 transgenes.Nature. 2011; 477: E1-E2Crossref PubMed Scopus (58) Google Scholar] and in Drosophila melanogaster [7Rogina B. Helfand S.L. Sir2 mediates longevity in the fly through a pathway related to calorie restriction.Proc. Natl. Acad. Sci. U.S.A. 2004; 101: 15998-16003Crossref PubMed Scopus (615) Google Scholar], and to mediate beneficial effects of calorie restriction (CR) on health and longevity[7Rogina B. Helfand S.L. Sir2 mediates longevity in the fly through a pathway related to calorie restriction.Proc. Natl. Acad. Sci. U.S.A. 2004; 101: 15998-16003Crossref PubMed Scopus (615) Google Scholar, 8Lin S.J. et al.Requirement of NAD and sir2 for life-span extension by calorie restriction in Saccharomyces cerevisiae.Science. 2000; 289: 2126-2128Crossref PubMed Scopus (965) Google Scholar, 9Lin S.J. et al.Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration.Nature. 2002; 418: 344-348Crossref PubMed Scopus (580) Google Scholar, 10Anderson R.M. et al.Yeast life-span extension by calorie restriction is independent of nad fluctuation.Science. 2003; 302: 2124-2126Crossref PubMed Scopus (97) Google Scholar]. These findings were challenged in 2011 by a study suggesting that SIR2 orthologs in worms and flies did not mediate increases in lifespan [11Burnett C. et al.Absence of effects of sir2 overexpression on lifespan in C. elegans and drosophila.Nature. 2011; 477: 482-485Crossref PubMed Scopus (190) Google Scholar]. As discussed in the next section, more recent studies in many organisms have now confirmed the original hypothesis that sirtuins are conserved, diet-sensitive, antiaging proteins.In mammals, the antiaging functions of sirtuins are conserved [12Kanfi Y. et al.The sirtuin sirt6 regulates lifespan in male mice.Nature. 2012; 483: 218-221Crossref PubMed Scopus (107) Google Scholar, 13Satoh A. et al.Sirt1 extends life span and delays aging in mice through the regulation of nk2 homeobox 1 in the dmh and lh.Cell Metab. 2013; 18: 416-430Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar]. There are seven mammalian sirtuins, SIRT1–7, which function to regulate metabolism in nonredundant ways in many tissues. Because sirtuins are located in distinct cellular compartments, they can coordinate cellular responses to CR throughout the organism. SIRT1, SIRT6, and SIRT7 are localized in the nucleus, where they function to deacetylate histones thereby influencing gene expression epigenetically [14Guarente L. Calorie restriction and sirtuins revisited.Genes Dev. 2013; 27: 2072-2085Crossref PubMed Scopus (3) Google Scholar]. SIRT1 also deacetylates specific transcription factors and enzymes to influence their activities, as described below. SIRT2 was originally described as a cytosolic sirtuin; however, recent data show that SIRT2 is also found in the nucleus where it functions to modulate cell cycle control [15Dryden S.C. et al.Role for human sirt2 NAD-dependent deacetylase activity in control of mitotic exit in the cell cycle.Mol. Cell. Biol. 2003; 23: 3173-3185Crossref PubMed Scopus (205) Google Scholar, 16Vaquero A. et al.Sirt2 is a histone deacetylase with preference for histone h4 lys 16 during mitosis.Genes Dev. 2006; 20: 1256-1261Crossref PubMed Scopus (189) Google Scholar, 17Serrano L. et al.The tumor suppressor sirt2 regulates cell cycle progression and genome stability by modulating the mitotic deposition of h4k20 methylation.Genes Dev. 2013; 27: 639-653Crossref PubMed Scopus (5) Google Scholar]. SIRT3, SIRT4, and SIRT5 are localized in mitochondria, and regulate the activities of metabolic enzymes and moderate oxidative stress in this organelle [18Verdin E. et al.Sirtuin regulation of mitochondria: energy production, apoptosis, and signaling.Trends Biochem. Sci. 2010; 35: 669-675Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar]. In general, SIRT3–5 respond to CR by switching cells to favor mitochondrial oxidative metabolism, along with the induction of accompanying stress tolerance.In this review, we focus our attention on SIRT1, the most studied sirtuin, but also touch briefly on other mammalian paralogs of SIRT1. We focus on the metabolic functions of SIRT1 and other sirtuins in critical tissues to mediate physiological adaptability to diets. We also discuss briefly some of the challenges and controversies that have emerged about the role of sirtuins in CR, and critically assess new findings that have begun to resolve these differences. Although we will not cover the large body of data on sirtuins and diabetes and neurodegenerative diseases, we will address the relationship between sirtuins and cancer. Finally, we will consider emerging findings on the importance of the sirtuin co-substrate NAD+ in aging and disease.The evolving role of sirtuins in CR and agingThe finding that sirtuins are NAD+-dependent deacetylases [1Imai S. et al.Transcriptional silencing and longevity protein sir2 is an NAD-dependent histone deacetylase.Nature. 2000; 403: 795-800Crossref PubMed Scopus (1470) Google Scholar] prompted the suggestion that they helped mediate the effects of CR in an active process. This idea contrasted with earlier proposals that CR extended lifespan by passive mechanisms, such as lowering the production of reactive oxygen species. In model organisms, nutrient limitation was shown to extend the lifespan via sirtuins in yeast, Drosophila, and C. elegans [19Chalkiadaki A. Guarente L. Sirtuins mediate mammalian metabolic responses to nutrient availability.Nat. Rev. Endocrinol. 2012; 8: 287-296Crossref PubMed Scopus (63) Google Scholar]. However, some laboratories observed lifespan extension by nutrient limitation that was independent of SIR2 orthologs [11Burnett C. et al.Absence of effects of sir2 overexpression on lifespan in C. elegans and drosophila.Nature. 2011; 477: 482-485Crossref PubMed Scopus (190) Google Scholar, 20Kaeberlein M. et al.Saccharomyces cerevisiae ssd1-v confers longevity by a sir2p-independent mechanism.Genetics. 2004; 166: 1661-1672Crossref PubMed Scopus (31) Google Scholar, 21Bishop N.A. Guarente L. Two neurons mediate diet-restriction-induced longevity in C. elegans.Nature. 2007; 447: 545-549Crossref PubMed Scopus (242) Google Scholar]. Part of the difficulty in interpreting these data is that laboratories may use a variety of protocols to limit nutrients. Another potential problem is differences in strain backgrounds among laboratories. Because several other nutrient sensors besides sirtuins exist, such as insulin signaling [22Kenyon C. A pathway that links reproductive status to lifespan in Caenorhabditis elegans.Ann. N. Y. Acad. Sci. 2010; 1204: 156-162Crossref PubMed Scopus (39) Google Scholar], target of rapamycin (TOR) [23Johnson S.C. et al.mTOR is a key modulator of ageing and age-related disease.Nature. 2013; 493: 338-345Crossref PubMed Scopus (58) Google Scholar], and AMP-activated protein kinase (AMPK) [24Kahn B.B. et al.Amp-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism.Cell Metab. 2005; 1: 15-25Abstract Full Text Full Text PDF PubMed Scopus (1192) Google Scholar], varied experimental conditions between different laboratories may activate different nutrient-sensing pathways. In the lower organisms, it therefore seems extremely likely that multiple pathways, including sirtuins, can elicit the benefits of nutrient limitation. In mice, the same murine strains are used under the same limitation of food of roughly the same composition. The lines of evidence that sirtuins mediate effects of CR in mammals are numerous and are outlined below.First, the non-histone proteins targeted for deacetylation by sirtuins closely define those pathways involved in metabolic adaptation to CR, for example oxidative metabolism in mitochondria (Figure 1) [14Guarente L. Calorie restriction and sirtuins revisited.Genes Dev. 2013; 27: 2072-2085Crossref PubMed Scopus (3) Google Scholar]. Second, CR induces the expression of the sirtuins: SIRT1 [25Cohen H.Y. et al.Calorie restriction promotes mammalian cell survival by inducing the sirt1 deacetylase.Science. 2004; 305: 390-392Crossref PubMed Scopus (918) Google Scholar], SIRT3 [26Lombard D.B. et al.Mammalian sir2 homolog sirt3 regulates global mitochondrial lysine acetylation.Mol. Cell. Biol. 2007; 27: 8807-8814Crossref PubMed Scopus (289) Google Scholar], and SIRT5 [27Nakagawa T. et al.Sirt5 deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycle.Cell. 2009; 137: 560-570Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar] in mice and SIRT1 in humans [28Civitarese A.E. et al.Calorie restriction increases muscle mitochondrial biogenesis in healthy humans.PLoS Med. 2007; 4: e76Crossref PubMed Scopus (283) Google Scholar]. Conversely, a high-fat diet can trigger the loss of SIRT1 in mice via proteolysis [29Chalkiadaki A. Guarente L. High-fat diet triggers inflammation-induced cleavage of sirt1 in adipose tissue to promote metabolic dysfunction.Cell Metab. 2012; 16: 180-188Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar], and obesity can reduce the expression of SIRT1 in humans [30Pedersen S.B. et al.Low sirt1 expression, which is upregulated by fasting, in human adipose tissue from obese women.Int. J. Obes. 2008; 32: 1250-1255Crossref Scopus (26) Google Scholar, 31Costa Cdos S. et al.Sirt1 transcription is decreased in visceral adipose tissue of morbidly obese patients with severe hepatic steatosis.Obes. Surg. 2010; 20: 633-639Crossref PubMed Scopus (22) Google Scholar]. Third, loss of function mutations in specific sirtuin genes can reduce specific outputs of CR. For example, SIRT1 knockout mice do not show the usual increase in physical activity induced by this diet [32Chen D. et al.Increase in activity during calorie restriction requires sirt1.Science. 2005; 310: 1641Crossref PubMed Scopus (241) Google Scholar]. In addition, brain-specific knockout of SIRT1 in mice does not show the characteristic changes in the somatotropic axis [growth hormone/insulin-like growth factor 1 (IGF-1)] induced by CR [33Cohen D.E. et al.Neuronal sirt1 regulates endocrine and behavioral responses to calorie restriction.Genes Dev. 2009; 23: 2812-2817Crossref PubMed Scopus (76) Google Scholar]. Most revealingly, SIRT1 knockout mice do not live longer on a CR diet [34Boily G. et al.Sirt1 regulates energy metabolism and response to caloric restriction in mice.PLoS ONE. 2008; 3: e1759Crossref PubMed Scopus (186) Google Scholar, 35Mercken E.M. et al.Sirt1 but not its increased expression is essential for lifespan extension in caloric restricted mice.Aging Cell. 2013; https://doi.org/10.1111/acel.12151Crossref Scopus (2) Google Scholar]. As for other sirtuins, knocking out the mitochondrial SIRT3 prevents the protective effect of CR against neuronal degeneration, leading to hearing loss [36Someya S. Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction.Cell. 2010; 143: 802-812Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar]. In this case, SIRT3 is required to reduce oxidative damage in crucial hair cell neurons of the cochlea. Deletion of the mitochondrial SIRT5 prevents the upregulation of the urea cycle, which is required to reduce blood ammonia when amino acids serve as energy sources [27Nakagawa T. et al.Sirt5 deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycle.Cell. 2009; 137: 560-570Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar]. SIRT3 null mice also show a defect in regulation of the urea cycle [37Hallows W.C. et al.Sirt3 promotes the urea cycle and fatty acid oxidation during dietary restriction.Mol. Cell. 2011; 41: 139-149Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar].A number of reports have also demonstrated that overexpression of SIRT1 in transgenic mice can mitigate disease syndromes much like CR, including diabetes, neurodegenerative diseases, liver steatosis, bone loss, and inflammation [38Baur J.A. et al.Resveratrol improves health and survival of mice on a high-calorie diet.Nature. 2006; 444: 337-342Crossref PubMed Scopus (1725) Google Scholar, 39Lagouge M. et al.Resveratrol improves mitochondrial function and protects against metabolic disease by activating sirt1 and pgc-1alpha.Cell. 2006; 127: 1109-1122Abstract Full Text Full Text PDF PubMed Scopus (1326) Google Scholar, 40Bordone L. et al.Sirt1 transgenic mice show phenotypes resembling calorie restriction.Aging Cell. 2007; 6: 759-767Crossref PubMed Scopus (307) Google Scholar, 41Pfluger P.T. et al.Sirt1 protects against high-fat diet-induced metabolic damage.Proc. Natl. Acad. Sci. U.S.A. 2008; 105: 9793-9798Crossref PubMed Scopus (298) Google Scholar, 42Herranz D. et al.Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer.Nat. Commun. 2010; 1: 3Crossref PubMed Scopus (55) Google Scholar]. Tissues responsible for these effects are shown in detail in Figure 1. Conversely, compromised sirtuin activity contributes to metabolic syndrome and diabetes, and exacerbates the effects of a high-fat diet in mice and humans [29Chalkiadaki A. Guarente L. High-fat diet triggers inflammation-induced cleavage of sirt1 in adipose tissue to promote metabolic dysfunction.Cell Metab. 2012; 16: 180-188Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar, 43Biason-Lauber A. et al.Identification of a sirt1 mutation in a family with type 1 diabetes.Cell Metab. 2013; 17: 448-455Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar]. In addition, SIRT1 activators like resveratrol [44Howitz K.T. et al.Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan.Nature. 2003; 425: 191-196Crossref PubMed Scopus (1565) Google Scholar] and newer sirtuin-activating compounds (STACs) [45Milne J.C. et al.Small molecule activators of sirt1 as therapeutics for the treatment of type 2 diabetes.Nature. 2007; 450: 712-716Crossref PubMed Scopus (693) Google Scholar] exert effects that are similar to those of CR, as revealed by measures of whole animal physiology [46Lam Y.Y. et al.Resveratrol vs. calorie restriction: data from rodents to humans.Exp. Gerontol. 2013; 48: 1018-1024Crossref PubMed Scopus (1) Google Scholar] or by transcriptional profiling [47Barger J.L. et al.A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice.PLoS ONE. 2008; 3: e2264Crossref PubMed Scopus (240) Google Scholar]. Importantly, a recent study strongly suggests that the effects of resveratrol and all 117 described STACs are direct and not artifacts of assays using fluorophore-containing peptides. STACs target an allosteric site in SIRT1, which is separate from the catalytic domain, and thus activate the deacetylation of substrates containing lysines with nearby hydrophobic residues [48Hubbard B.P. et al.Evidence for a common mechanism of sirt1 regulation by allosteric activators.Science. 2013; 339: 1216-1219Crossref PubMed Scopus (54) Google Scholar]. In toto these data comprise a compelling set of evidence that suggests sirtuins are fundamentally involved in mediating effects of CR.Although a paper by Burnett et al. [11Burnett C. et al.Absence of effects of sir2 overexpression on lifespan in C. elegans and drosophila.Nature. 2011; 477: 482-485Crossref PubMed Scopus (190) Google Scholar] did not find lifespan extension in SIR2 ortholog transgenic lines of C. elegans or Drosophila, many other studies have established such a connection [5Tissenbaum H.A. Guarente L. Increased dosage of a sir-2 gene extends lifespan in caenorhabditis elegans.Nature. 2001; 410: 227-230Crossref PubMed Scopus (1026) Google Scholar, 6Viswanathan M. Guarente L. Regulation of caenorhabditis elegans lifespan by sir-2.1 transgenes.Nature. 2011; 477: E1-E2Crossref PubMed Scopus (58) Google Scholar, 7Rogina B. Helfand S.L. Sir2 mediates longevity in the fly through a pathway related to calorie restriction.Proc. Natl. Acad. Sci. U.S.A. 2004; 101: 15998-16003Crossref PubMed Scopus (615) Google Scholar, 10Anderson R.M. et al.Yeast life-span extension by calorie restriction is independent of nad fluctuation.Science. 2003; 302: 2124-2126Crossref PubMed Scopus (97) Google Scholar, 49Wood J.G. et al.Sirtuin activators mimic caloric restriction and delay ageing in metazoans.Nature. 2004; 430: 686-689Crossref PubMed Scopus (883) Google Scholar, 50Berdichevsky A. et al.C. elegans sir-2.1 interacts with 14-3-3 proteins to activate daf-16 and extend life span.Cell. 2006; 125: 1165-1177Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar, 51Rizki G. et al.The evolutionarily conserved longevity determinants hcf-1 and sir-2.1/sirt1 collaborate to regulate daf-16/foxo.PLoS Genet. 2011; 7: e1002235Crossref PubMed Scopus (30) Google Scholar]. During the past year, new studies were reported confirming the importance of SIR2 orthologs in slowing aging and extending lifespan in yeast [52Stumpferl S.W. et al.Natural genetic variation in yeast longevity.Genome Res. 2012; 22: 1963-1973Crossref PubMed Scopus (8) Google Scholar], C. elegans [53Ludewig A.H. et al.Pheromone sensing regulates caenorhabditis elegans lifespan and stress resistance via the deacetylase sir-2.1.Proc. Natl. Acad. Sci. U.S.A. 2013; 110: 5522-5527Crossref PubMed Scopus (3) Google Scholar, 54Mouchiroud L. et al.The NAD(+)/sirtuin pathway modulates longevity through activation of mitochondrial upr and foxo signaling.Cell. 2013; 154: 430-441Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar], and Drosophila [55Banerjee K.K. et al.Dsir2 in the adult fat body, but not in muscles, regulates life span in a diet-dependent manner.Cell Rep. 2012; 2: 1485-1491Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar]. Extension of murine lifespan has also been reported for transgenic lines of SIRT6 [12Kanfi Y. et al.The sirtuin sirt6 regulates lifespan in male mice.Nature. 2012; 483: 218-221Crossref PubMed Scopus (107) Google Scholar] or SIRT1 [13Satoh A. et al.Sirt1 extends life span and delays aging in mice through the regulation of nk2 homeobox 1 in the dmh and lh.Cell Metab. 2013; 18: 416-430Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar]. Thus, there is also compelling evidence that sirtuins regulate aging, which is consistent with their important role in CR.Metabolic regulation in the liverWhole body glucose homeostasis is critically regulated by the liver. When blood glucose levels are low, due to fasting or CR, hepatic metabolism immediately shifts to glycogen breakdown and then gluconeogenesis to ensure glucose supply and ketone body production to bridge energy deficits. Fasting also activates muscle and liver oxidation of fatty acids produced by lipolysis in white adipose tissue (WAT). Several transcription factors are involved in a sophisticated switch to adapt to energy deprivation, and SIRT1 mediates the metabolic switch during fasting (Figure 1) [56Liu Y. et al.A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange.Nature. 2008; 456: 269-273Crossref PubMed Scopus (189) Google Scholar]. During the initial (post-glycogen breakdown) phase of fasting, pancreatic alpha cells produce glucagon to activate gluconeogenesis systemically in the liver via the cyclic AMP response-element-binding protein (CREB) and its coactivator: CREB-regulated transcription coactivator 2 (CRTC2). During more prolonged fasting, however, this effect is cancelled by SIRT1-mediated CRTC2 deacetylation, which targets the coactivator for ubiquitin/proteasome–mediated destruction [56Liu Y. et al.A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange.Nature. 2008; 456: 269-273Crossref PubMed Scopus (189) Google Scholar]. SIRT1 then triggers the next stage of gluconeogenesis by deacetylating and activating the peroxisome proliferator-activated receptor (PPAR)γ coactivator 1α (PGC-1α), a coactivator for forkhead box O1 (FOXO1) [57Rodgers J.T. et al.Nutrient control of glucose homeostasis through a complex of pgc-1alpha and sirt1.Nature. 2005; 434: 113-118Crossref PubMed Scopus (1147) Google Scholar]. Besides supporting gluconeogenesis, PGC-1α is also important for mitochondrial biogenesis, which assists the liver in accommodating the reduced energy status. Meanwhile, to increase energy production, SIRT1 stimulates fatty acid oxidation by deacetylating and activating the nuclear receptor, PPARα [58Purushotham A. et al.Hepatocyte-specific deletion of sirt1 alters fatty acid metabolism and results in hepatic steatosis and inflammation.Cell Metab. 2009; 9: 327-338Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar]. SIRT1 can also shut down the production of energy via glycolysis by deacetylating and repressing glycolytic enzymes, for example phosphoglycerate mutase-1 (PGAM-1) [59Hallows W.C. et al.Regulation of glycolytic enzyme phosphoglycerate mutase-1 by sirt1 protein-mediated deacetylation.J. Biol. Chem. 2012; 287: 3850-3858Crossref PubMed Scopus (12) Google Scholar]. Interestingly, another nuclear sirtuin, SIRT6, has also been reported to repress glycolysis by serving as a co-repressor for hypoxia-inducible factor 1α (HIF-1α) [60Zhong L. et al.The histone deacetylase sirt6 regulates glucose homeostasis via hif1alpha.Cell. 2010; 140: 280-293Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar]. Because SIRT6 itself is transcriptionally activated by SIRT1, sirtuins might regulate cellular physiology in a coordinated way to determine the duration of each phase of fasting [61Kim H.S. et al.Hepatic-specific disruption of sirt6 in mice results in fatty liver formation due to enhanced glycolysis and triglyceride synthesis.Cell Metab. 2010; 12: 224-236Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar].In addition to glucose homeostasis, the liver plays important roles in controlling lipid and cholesterol homeostasis. During fasting, fat and cholesterol synthesis in the liver is turned off, and lipolysis in WAT is favored. The major hepatic transcription factors for lipogenesis and cholesterol synthesis are proteins belonging to the sterol regulatory element binding protein (SREBP) family [62Horton J.D. et al.SREBPS: activators of the complete program of cholesterol and fatty acid synthesis in the liver.J. Clin. Invest. 2002; 109: 1125-1131Crossref PubMed Google Scholar]. Upon fasting, SIRT1 deacetylates SREBP1 and targets the protein for destruction through the ubiquitin–proteasome system (Figure 1) [63Walker A.K. et al.Conserved role of sirt1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator srebp.Genes Dev. 2010; 24: 1403-1417Crossref PubMed Scopus (80) Google Scholar]. The result is repression of fat and cholesterol synthesis, consistent with the finding that SIRT1 liver-specific knockout mice develop hepatic steatosis [58Purushotham A. et al.Hepatocyte-specific deletion of sirt1 alters fatty acid metabolism and results in hepatic steatosis and inflammation.Cell Metab. 2009; 9: 327-338Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar]. For regulating cholesterol homeostasis, SIRT1 also regulates the oxysterol receptor (LXRα) to assist in reverse cholesterol transport from peripheral tissues by upregulating the LXRα target gene ATP-binding cassette transporter A1 (ABCA1) [64Li X. et al.Sirt1 deacetylates and positively regulates the nuclear receptor lxr.Mol. Cell. 2007; 28: 91-106Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar]. The cholesterol regulatory loop can be further modulated through the bile acid receptor, that is, farnesoid X receptor (FXR), which is important for biosynthesis of bile acids and cholesterol catabolic pathways. SIRT1 deacetylates and activates FXR [65Kemper J.K. et al.Fxr acetylation is normally dynamically regulated by p300 and sirt1 but constitutively elevated in metabolic disease states.Cell Metab. 2009; 10: 392-404Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar], and FXR can also upregulate SIRT1 by repressing the SIRT1-targeting microRNA mir-34a [66Lee J. et al.A pathway involving farnesoid x receptor and small heterodimer partner positively regulates hepatic sirtuin 1 levels via microrna-34a inhibition.J. Biol. Chem. 2010; 285: 12604-12611Crossref PubMed Scopus (56) Google Scholar]. Similarly, SIRT6 appears to regulate cholesterol levels by repressing SREBP1/2, both at the level of their expression and their post-translational cleavage into the active form [67Tao R. et al.Hepatic srebp-2 and cholesterol biosynthesis are regulated by foxo3 and sirt6.J. Lipid Res. 2013; 54: 2745-2753Crossref PubMed Scopus (2) Google Scholar, 68Elhanati S. et al.Multiple regulatory layers of srebp1/2 by sirt6.Cell Rep. 2013; 4: 905-912Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar]. These results again point out collaborative roles of nuclear sirtuins, in this case in hepatic lipid metabolism. Finally, SIRT1 plays an important role in maintaining circadian regulation of metabolic processes in the liver by regulating the cell autonomous, circadian clock in that tissue [69Asher G. et al.Sirt1 regulates circadian clock gene expression through per2 deacetylation.Cell. 2008; 134: 317-328Abstract Full Text Full Text PDF PubMed Scopus (338) Google Scholar, 70Nakahata Y. et al.The NAD+-dependent deacetylase sirt1 modulates clock-mediated chromatin remodeling and circadian control.Cell. 2008; 134: 329-340Abstract Full Text Full Text PDF PubMed Scopus (370) Google Scholar]. This regulation involves the deacetylation of two central components of the clock, BMAL1 (Brain and Muscle ARNT-Like 1) and PER2 (Period 2), in the liver.Besides nuclear sirtuins, mitochondrial SIRT3 is critical in fatty acid oxidation in the mitochondria. Upon fasting or calorie restriction, SIRT3 protein level a" @default.
• W2056564149 created "2016-06-24" @default.
• W2056564149 creator A5013771208 @default.
• W2056564149 creator A5091256879 @default.
• W2056564149 date "2014-03-01" @default.
• W2056564149 modified "2023-10-17" @default.
• W2056564149 title "SIRT1 and other sirtuins in metabolism" @default.
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