Modulation Of SIRT1 Research Articles

Sirt1 activation by resveratrol is substrate sequence-selective

Sirtuins are protein deacetylases used as therapeutic targets. Pharmacological Sirt1 activation has been questioned since the in vitro activator resveratrol failed to stimulate deacetylation of several physiological substrates. We tested the influence of substrate sequence by analyzing resveratrol effects on Sirt1-dependent deacetylation of 6802 physiological acetylation sites using peptide microarrays. Resveratrol stimulated deacetylation of a small set of sites and inhibited deacetylation of another set, whereas most substrates were hardly affected. Solution assays confirmed these substrate categories, and statistical analysis revealed their sequence features. Our results reveal substrate sequence dependence for Sirt1 modulation and suggest substrates contributing to resveratrol effects.

The SIRT1 Modulators AROS and DBC1 Regulate HSF1 Activity and the Heat Shock Response

The heat shock response, the cellular response to protein damaging stress, is critical in maintaining proteostasis. The heat shock response is regulated by the transcription factor HSF1, which is activated upon heat shock and other stresses to induce the expression of molecular chaperones. SIRT1 has previously been shown to activate HSF1 by deacetylating it, leading to increased DNA binding ability. We have investigated how the heat shock response may be controlled by factors influencing SIRT1 activity. We found that heat shock results in an increase in the cellular NAD+/NADH ratio and an increase in recruitment of SIRT1 to the hsp70 promoter. Furthermore, we found that the SIRT1 modulators AROS and DBC1 have an impact on hsp70 transcription, HSF1 acetylation status, and HSF1 recruitment to the hsp70 promoter. Therefore, AROS and DBC1 are now two new targets available for therapeutic regulation of the heat shock response.

Sirt1 Mediates Hyperbaric Oxygen Preconditioning-Induced Ischemic Tolerance in Rat Brain

Our previous studies have shown that hyperbaric oxygen preconditioning (HBO-PC) induces tolerance to cerebral ischemia/reperfusion (I/R). This study aimed to investigate whether SirT1, a class III histone deacetylase, is involved in neuroprotection elicited by HBO-PC in animal and cell culture models of ischemia. Rats were subjected to middle cerebral artery occlusion for 120 minutes after HBO-PC (once a day for 5 days). Primary cultured cortical neurons were exposed to 2 hours of HBO-PC after 2 hours of oxygen–glucose deprivation (OGD). We showed that HBO-PC increased SirT1 protein and mRNA expression, promoted neurobehavioral score, reduced infarct volume, and improved morphology at 24 hours and 7 days after cerebral I/R. Neuroprotection of HBO-PC was attenuated by SirT1 inhibitor EX527 and SirT1 knockdown by short interfering RNA (siRNA), whereas it was mimicked by SirT1 activator resveratrol. Furthermore, HBO-PC enhanced SirT1 expression and cell viability and reduced lactate dehydrogenase release 24 hours after OGD/re-oxygenation. The neuroprotective effect of HBO-PC was emulated through upregulating SirT1 and, reversely, attenuated through downregulating SirT1. The modulation of SirT1 was made by adenovirus infection carrying SirT1 or SirT1 siRNA. Besides, SirT1 increased B-cell lymphoma 2 (Bcl-2) expression and decrease cleaved caspase 3. These results indicate that SirT1 mediates HBO-PC-induced tolerance to cerebral I/R through inhibition of apoptosis.

SIRT1 Protects Dendrites, Mitochondria and Synapses from Aβ Oligomers in Hippocampal Neurons

Aging is a major risk factor in the onset of neurodegenerative diseases, such as Alzheimer’s disease (AD). SIRT1, a β-NAD+-dependent histone deacetylase activity, holds great potential for promoting longevity, preventing against disease and increasing cell survival. We report here, that SIRT1 protects against the damage caused by Aβ oligomers at the level of synaptic contacts, dendritic branching and mitochondrial structure in cultured rat hippocampal neurons. Neurons overexpressing SIRT1 showed increased synaptic contacts, dendritic branching and preserved mitochondrial morphology, suggesting the prevention of the Aβ oligomer-mediated neurodegeneration. Such effects were not observed in neurons overexpressing a dominant negative form of SIRT1. The potential underlying signaling pathways involved in the SIRT1 neuroprotective mechanism are discussed in the context of the peroxisome proliferator-activated receptors (PPARs), peroxisome proliferator activated receptor co-activator 1α (PGC-1α), mTOR, and the Wnt signaling pathway. Our results suggest that SIRT1 modulation might well be a therapeutic agent to protect against neurodegenerative diseases, like AD.

A derivative of the CRMP2 binding compound lanthionine ketimine provides neuroprotection in a mouse model of cerebral ischemia

Lanthionines are novel neurotrophic and neuroprotective small molecules that show promise for the treatment of neurodegenerative diseases. In particular, a recently developed, cell permeable lanthionine derivative known as LKE (lanthionine ketimine 5-ethyl ester) promotes neurite growth at low nanomolar concentrations. LKE also has neuroprotective, anti-apoptotic, and anti-inflammatory properties. Its therapeutic potential in cerebral ischemia and its mechanisms of neurotrophic action remain to be fully elucidated. Here, we hypothesize that the neuroprotective actions of LKE could result from induction or modulation of CRMP2. We found that treating primary cultured mouse neurons with LKE provided significant protection against t-butyl hydroperoxide-induced neuronal death possibly through CRMP2 upregulation. Similarly, in vivo studies showed that LKE pre and/or post-treatment protects mice against permanent distal middle cerebral artery occlusion (p-MCAO) as evidenced by lower stroke lesions and improved functional outcomes in terms of rotarod, grip strength and neurologic deficit scores in treated groups. Protein expression levels of CRMP2 were higher in brain cortices of LKE pretreated mice, suggesting that LKE’s neuroprotective activity may be CRMP2 dependent. Lower activity of cleaved PARP-1 and higher activity of SIRT-1 was also observed in LKE treated group suggesting its anti-apoptotic properties. Our results suggest that LKE has potential as a therapeutic intervention in cerebral ischemia and that part of its protective mechanism may be attributed to CRMP2 mediated action and PARP-1/SIRT-1 modulation.

Resveratrol Mediated Modulation of Sirt-1/Runx2 Promotes Osteogenic Differentiation of Mesenchymal Stem Cells: Potential Role of Runx2 Deacetylation

ObjectiveOsteogenic repair in response to bone injury is characterized by activation and differentiation of mesenchymal stem cells (MSCs) to osteoblasts. This study determined whether activation of Sirt-1 (a NAD+-dependent histone deacetylase) by the phytoestrogen resveratrol affects osteogenic differentiation.MethodsMonolayer and high-density cultures of MSCs and pre-osteoblastic cells were treated with an osteogenic induction medium with/without the Sirt-1 inhibitor nicotinamide or/and resveratrol in a concentration dependent manner.ResultsMSCs and pre-osteoblastic cells differentiated to osteoblasts when exposed to osteogenic-induction medium. The osteogenic response was blocked by nicotinamide, resulting in adipogenic differentiation and expression of the adipose transcription regulator PPAR-γ (peroxisome proliferator-activated receptor). However, in nicotinamide-treated cultures, pre-treatment with resveratrol significantly enhanced osteogenesis by increasing expression of Runx2 (bone specific transcription factor) and decreasing expression of PPAR-γ. Activation of Sirt-1 by resveratrol in MSCs increased its binding to PPAR-γ and repressed PPAR-γ activity by involving its cofactor NCoR (nuclear receptor co-repressor). The modulatory effects of resveratrol on nicotinamide-induced expression of PPAR-γ and its cofactor NCoR were found to be mediated, at least in part, by Sirt-1/Runx2 association and deacetylation of Runx2.Finally, knockdown of Sirt-1 by using antisense oligonucleotides downregulated the expression of Sirt-1 protein and abolished the inhibitory effects of resveratrol, namely nicotinamide-induced Sirt-1 suppression and Runx2 acetylation, suggesting that the acetylated content of Runx2 is related to downregulated Sirt-1 expression.ConclusionThese data support a critical role for Runx2 acetylation/deacetylation during osteogenic differentiation in MSCs in vitro. (242 words in abstract)

Examination of the reproductive effects of SirT1 expression in neurons

Caloric restriction (CR) in females often leads to a decrease in reproductive function and it is thought that SirT1 mediates the effects of CR at the cellular level. We hypothesize that SirT1 acts as a trigger for reproductive inhibition during CR. To test this hypothesis, we generated two mouse models. The first model overexpresses SirT1 (OX) to mimic times of CR and the second model expresses a deleted SirT1 lacking the catalytic domain (KO) rendering the protein inactive and as such should be resistant to CR. Both models are neuron specific through the use of a synapsin‐driven cre recombinase mouse to excise either a floxed‐STOP or the floxed‐catalytic domain. Modulation of SirT1 in neurons alters body weight in both the overexpressing and knockout models. We will present data on estrous cyclicity, endocrine and steroid hormone levels, and fertility in these animals and on the effects of CR on the knockout model. This research is supported by NIH grants U54HD12303 and T32 DK007494.

Sirtuin1 in tracheal aspirate leukocytes: possible role in the development of bronchopulmonary dysplasia in premature infants

Objective: To study the association between Sirtuin1 (Sirt1), a class III histone deacetylator, in tracheal aspirate (TA) leukocytes and the development of bronchopulmonary dysplasia (BPD) in premature infants and modulation of Sirt1 with dexamethasone (Dex) use. Design/methods: Serial TA samples were collected on days 1, 3, 5 and 7 from ventilated premature neonates. Sirt1 was localized by immunocytochemistry and quantified on a scale of 0–4 by blinded observers. BPD was defined as the need of supplemental oxygen at 36 weeks postmenstrual age (PMA). Results: A total of 130 TA samples were collected from 51 infants (mean ± SD: GA 25.5 ± 1.4 w, BW 762 ± 174 g). Eleven infants survived without BPD and 40 infants died before 36 weeks PMA or developed BPD. Sirt1 was localized in the cytoplasm and nuclei of mononuclear (MONO) as well as polymorphonuclear cells. Sirt1 was significantly more localized in the nuclei of MONO cells in infants without BPD compared to infants who developed BPD or died before 36 weeks PMA. Twenty six infants received Dex. There was no significant change in Sirt1 localization with steroid therapy. Conclusions: Lower Sirt1 in TA leukocytes is associated with the development of BPD or death in premature infants. Dex use had no effect on Sirt1.

Xanthigen Suppresses Preadipocyte Differentiation and Adipogenesis through Down-regulation of PPARγ and C/EBPs and Modulation of SIRT-1, AMPK, and FoxO Pathways

Xanthigen is a source of punicic acid and fucoxanthin derived from pomegranate seed and brown seaweed, respectively with recognized triacylglycerol-lowering effects in humans, yet the mechanism remains to be fully elucidated. The present study investigated the inhibitory effects of Xanthigen, fucoxanthin, and punicic acid (70% in pomegranate seed oil) on the differentiation of 3T3-L1 preadipocytes. Xanthigen potently and dose-dependently suppressed accumulation of lipid droplets in adipocytes compared to its individual components, fucoxanthin and pomegranate seed oil. Western blot analysis revealed that Xanthigen markedly down-regulated the protein levels of key adipogenesis transcription factors peroxisome proliferator-activated receptor (PPAR)γ, CCAAT/enhancer binding protein (C/EBP) β, and C/EBPδ as well as a key enzyme involved in adipogenesis, fatty acid synthase (FAS). Xanthigen up-regulated the NAD(+)-dependent histone deacetylases (SIRT1) and activated AMP-activated protein kinase (AMPK) signaling in differentiated 3T3-L1 adipocytes. In addition, Xanthigen may also stimulate insulin trigger signaling and result in Akt-dependent phosphorylation of forkhead/winged helix O (FoxO)1 and FoxO3a. These results indicate that Xanthigen suppresses adipocyte differentiation and lipid accumulation through multiple mechanisms and may have applications for the treatment of obesity.

Poly(ADP‐ribose) polymerase 1 is involved in glucose toxicity through SIRT1 modulation in HepG2 hepatocytes

Accelerated glucose metabolism leads to oxidative stress and DNA damage in cells; these effects are related to glucose toxicity. The precise mechanisms of glucose toxicity are still unclear. The aim of this work was to investigate the mechanism of poly(ADP-ribose) polymerase 1 (PARP1), which is a DNA repair enzyme activated by high-glucose-induced oxidative stress, and its effect on glucose toxicity in HepG2 hepatocytes. HepG2 cells were cultured under normal (5.5 mM) or high (30 mM) glucose conditions for 4 days. PJ34, which is an inhibitor of PARP1, was used to determine the downstream effects of PARP1 activation. PARP1 activity in 30 mM-glucose-treated cells was more than that in 5.5 mM-glucose-treated cells, and the activity correlated with the increase in ROS generation and DNA damage. PJ34 suppressed PARP1 activation and prevented the high-glucose-induced suppression of SIRT1 and AMP-activated protein kinase (AMPK) activity, which was similar to its effect on the restoration of intracellular nicotinamide adenine dinucleotide (NAD) content. Further, the phosphorylation of insulin receptor was attenuated in response to insulin stimulation under high glucose conditions, and PJ34 could reverse this effect. The results of transfection of HepG2 cells with PARP1 small interfering RNA were similar to those obtained by treatment of the cells with PARP1 inhibitor PJ34. These data suggest that high-glucose-induced PARP1 activation might play a role in glucose toxicity by down-regulating SIRT1 and AMPK activity through NAD depletion and resulting in insulin insensitivity.

Viral genome silencing by neuronal sirtuin 1

Neurotropic viruses remain dormant in sensory neurons for years, but upon reactivation, they can produce multiple disease states including pain symptoms. Latent viral DNA is extrachromosomal, maintained as a circular episome bound to histones. Here, we show the regulation of an adenoviral genome by the nicotinamide adenine dinucleotide (NAD(+))-dependent histone deacetylator Sirt1 in dorsal root ganglion neurons. Pharmacological modulation of Sirt1 and Sirt1 overexpression both affected viral transgene expression. We propose that age or stress-related neuronal NAD(+) depletion may be a trigger for viral reactivation.

SIRT1 Modulation as a Novel Approach to the Treatment of Diseases of Aging

SIRT1 Modulation as a Novel Approach to the Treatment of Diseases of Aging

Sirt1 inhibition promotes in vivo arterial thrombosis and tissue factor expression in stimulated cells

The mammalian silent information regulator-two 1 (Sirt1) blunts the noxious effects of cardiovascular risk factors such as type 2 diabetes mellitus and obesity. Nevertheless, the role of Sirt1 in regulating the expression of tissue factor (TF), the key trigger of coagulation, and arterial thrombus formation remains unknown. Human as well as mouse cell lines were used for in vitro experiments, and C57Bl/6 mice for in vivo procedures. Sirt1 inhibition by splitomicin or sirtinol enhanced cytokine-induced endothelial TF protein expression as well as surface activity, while TF pathway inhibitor protein expression did not change. Sirt1 inhibition further enhanced TF mRNA expression, TF promoter activity, and nuclear translocation as well as DNA binding of the p65 subunit of nuclear factor-kappa B (NFκB/p65). Sirt1 siRNA enhanced TF protein and mRNA expression, and this effect was reduced in NFκB/p65(-/-) mouse embryonic fibroblasts reconstituted with non-acetylatable Lys(310)-mutant NFκB/p65. Activation of the mitogen-activated protein kinases p38, c-Jun NH(2)-terminal kinase, and p44/42 (ERK) remained unaffected. In vivo, mice treated with the Sirt1 inhibitor splitomicin exhibited enhanced TF activity in the arterial vessel wall and accelerated carotid artery thrombus formation in a photochemical injury model. We provide pharmacological and genetic evidence that Sirt1 inhibition enhances TF expression and activity by increasing NFκB/p65 activation in human endothelial cells. Furthermore, Sirt1 inhibition induces arterial thrombus formation in vivo. Hence, modulation of Sirt1 may offer novel therapeutic options for targeting thrombosis.

An Energy-Sensor Network Takes Center Stage During Endothelial Aging

See related article, pages 1384–1393 Blood vessels form a critical interface between the environment and the organism by supplying nutrients, oxygen and macromolecules to all tissues and cells in the body. Endothelial cells (ECs) line the inner surface of the hierarchically branched blood vessel network and integrate functionally into different organs to support tissue growth and function in development, physiology, and disease. In healthy postnatal tissues, ECs are mostly quiescent and rarely migrate or proliferate. However, ECs possess a remarkable phenotypic plasticity in terms of being able to proliferate rapidly in response to vascular injury, tissue ischemia, or other stress conditions. This phenotypic plasticity progressively declines when ECs age and/or are permanently exposed to metabolic (eg, hyperglycemia) and environmental stressors (eg, oxidative stress) and coincides with the development of endothelial senescence.1 Cellular senescence is a stress response that is characterized by a robust inhibition of cell proliferation, which often becomes irreversible and independent of the initial stress signal.2 Senescence can be observed in most mammalian cells after extended propagation in culture and is related to the attrition of telomeres after repetitive cycles of cell divisions.2 In addition to telomere shortening, other stressors such as DNA damage, genomic instability, and oxidative stress can induce a similar growth arrest and trigger senescence.2 Senescent cells display characteristic alterations in cell morphology and gene expression that may weaken cellular functions. In ECs, these changes cause a phenotype that is proinflammatory, prothrombotic, and proatherosclerotic, which also negatively affects the vasodilatory, angiogenic, and regenerative properties of ECs and, thus, accelerates the development of several cardiovascular diseases.1 Despite advances in understanding the molecular mechanisms of endothelial senescence and vascular aging, the signaling networks governing the development and progression of EC senescence remain less well defined. In this issue of Circulation Research …

Comparative deacetylase activity of wild type and mutants of SIRT1

SIRT1, human ortholog of yeast SIR2 protein, deacetylates histones and several other transcription factors. Recently, SIRT1 has emerged as a drug target for treating age related diseases, type II diabetes, neurodegeneration, inflammation and cancer. Here, we have optimized production of functionally active wild type full-length SIRT1 protein and its N-terminal deleted mutants. In a comparative study, we found that the region containing 192–208 amino acids towards the N-terminus is critical for right conformational folding of the protein to retain its deacetylase activity. The EC50 and IC50 values obtained with standard modulators showed that the SRT748 & SRT556 can deacetylate substrate and are activated by resveratrol, whereas, deacetylase activity of all the other deletion mutants (SRT540, SRT532, SRT507 and SRT503) was lost. We further report that the peptide substrate Km for SRT748 (70±5.2μM) was comparable to SRT556 (93±5.4μM). The Km for NAD+ substrate was 176 & 274μM for SRT748 and SRT556, respectively. Similar substrate affinity studies demonstrate that either of the protein (SRT748 or SRT556) can be utilized for screening SIRT1 modulators. We have also examined critical regions in SIRT1 required for deacetylase activity as well as kinetic analyses of SIRT1 proteins.

Sirolimus and Everolimus Induce Endothelial Cellular Senescence Via Sirtuin 1 Down-Regulation: Therapeutic Implication of Cilostazol After Drug-Eluting Stent Implantation

The aim of this study was to compare the effects of paclitaxel, sirolimus, and everolimus on the senescent phenotype in human endothelial cells, and to further investigate possible involvement of mammalian sirtuin 1 (Sirt1) down-regulation as a mechanism. Endothelial cell senescence may play a role in impaired re-endothelialization after drug-eluting stent (DES) implantation. Recently, the down-regulation of Sirt1 has been shown to mediate oxidative stress-induced endothelial senescence. Senescent human umbilical vein endothelial cells (HUVEC) were judged by senescence-associated beta-galactosidase assay (SA-betagal), morphological appearance, and plasminogen activator inhibitor (PAI)-1. Treatment with paclitaxel, sirolimus, and everolimus significantly caused a senescent phenotype and PAI-1 up-regulation, associated with a decrease in endothelial nitric oxide synthase (eNOS) and Sirt1 expression. Overexpression of Sirt1 or Sirt1 activation reversed the sirolimus- or everolimus-induced senescent phenotype. Interestingly, paclitaxel-induced senescence was not suppressed by Sirt1 overexpression, suggesting the existence of a different mechanism. Cilostazol markedly inhibited the sirolimus- or everolimus-induced senescent phenotype (sirolimus or everolimus [2.5 nmol/l]; 49.2% or 53.0% SA-betagal positive vs. only 13.6% or 14.6% with cilostazol [100 micromol/l]) and PAI-1 up-regulation, but had no influence on the effects of paclitaxel. Finally, aspirin significantly blunted sirolimus- or everolimus-induced senescence, but neither ticlopidine nor clopidogrel had any effects. Sirolimus and everolimus induce endothelial senescence involving down-regulation of Sirt1. In contrast, the development of endothelial senescence by paclitaxel involves a Sirt1-independent pathway. Because sirolimus and everolimus are involved in Sirt1 modulation, cilostazol rescues HUVEC from sirolimus- or everolimus-induced senescence. These results may have therapeutic implications in the clinical sequelae after DES implantation.

SIRT1 genetic variation and mortality in type 2 diabetes: interaction with smoking and dietary niacin

SIRT1 protects cells against oxidative stress and aging. Its activity may be modulated by dietary niacin (vitamin B3) intake. We studied the association of SIRT1 genetic variation with mortality in subjects with increased oxidative stress (type 2 diabetes and smokers) in relation to dietary niacin. In 4573 participants from the Rotterdam Study, including 413 subjects with prevalent and 378 with incident type 2 diabetes, three SIRT1 tagging SNPs were genotyped and all-cause mortality was studied (average follow-up12 years). We found no association between SIRT1 variation and mortality in the total population or in smokers. In subjects with prevalent type 2 diabetes, homozygous carriers of the most common SIRT1 haplotype, 1, had 1.5 times (95%CI 1.1–2.1) increased mortality risk compared to noncarriers. This risk further increased among smokers and those with low niacin intake. In the lowest tertile of niacin intake, mortality risk was increased 2.3 (95%CI 1.1–4.9) and 5.7 (95%CI 2.5–13.1) times for heterozygous and homozygous carriers of haplotype 1. Subjects with incident diabetes showed similar findings but only when they smoked. We conclude that in subjects with type 2 diabetes, SIRT1 genetic variation influences survival in interaction with dietary niacin and smoking. Correction of niacin deficiency and SIRT1 modulators may prolong the life span of patients with diabetes.

Modulation of the longevity proteins FOXO3a and SIRT1 by chorionic gonadotropin prevents hepatocellular injury during acute liver inflammation

Modulation of the longevity proteins FOXO3a and SIRT1 by chorionic gonadotropin prevents hepatocellular injury during acute liver inflammation

A Review of Sirt1 and Sirt1 Modulators in Cardiovascular and Metabolic Diseases

Sirt1 (member of the sirtuin family) is a nicotinamide adenosine dinucleotide (NAD)-dependent deacetylase that removes acetyl groups from various proteins. A wide variety of proteins are Sirt1 substrates; the list includes many transcription factors and cofactors. Deacetylation of these factors may lead to activation or inactivation of the factor, thus impacting downstream gene expression. In addition to direct deacetylation, Sirt1 can modulate protein activity by other mechanisms. Although initial research focused on sirtuin's role in life span extension especially in lower organisms more recent studies show that Sirt1 activity can impact a wide array of proteins implicated in cardiovascular (CV) and metabolic diseases. Several patents have been published in the last 5 years describing the application of sirtuin compounds in the treatment of metabolic diseases. This review will focus on those Sirt1-modifiable proteins that have an impact on CV and metabolic diseases. Pharmacological agents that activate Sirt1 and thus impact the disease process will also be reviewed.

Modulation of Sirt1 by resveratrol and nicotinamide alters proliferation and differentiation of pig preadipocytes

Sirt1, a NAD(+)-dependent histone deacetylase, may regulate senescence, metabolism, and apoptosis. In this study, primary pig preadipocytes were cultured in DMEM/F12 medium containing 10% fetal bovine serum (FBS) with or without reagents affecting Sirt1 activity. The adipocyte differentiation process was visualized by light microscopy after Oil red O staining. Proliferation and differentiation of preadipocytes was measured using methylthiazolyldiphenyl-tetrazolium bromide (MTT) and Oil red O extraction. Expression of Sirt1, FoxO1, and adipocyte specific genes was detected with semi-quantitive RT-PCR. The results showed that Sirt1 mRNA was widely expressed in various pig tissues from different developmental stages. Sirt1 mRNA was expressed throughout the entire differentiation process of pig preadipocytes. Resveratrol significantly increased Sirt1 mRNA expression, but decreased the expression of FoxO1 and adipocyte marker gene PPARgamma2. Resveratrol significantly inhibited pig preadipocyte proliferation and differentiation. Nicotinamide decreased the expression of Sirt1 mRNA, but increased the expression of FoxO1 and adipocyte specific genes. Nicotinamide greatly stimulated the proliferation and differentiation of pig preadipocytes. In conclusion, these results indicate that Sirt1 may modulate the proliferation and differentiation of pig preadipocytes. Sirt1 may down-regulate pig preadipocytes proliferation and differentiation through repression of adipocyte genes or FoxO1.