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Modulatory effect of resveratrol on SIRT1, SIRT3, SIRT4, PGC1α and NAMPT gene expression profiles in wild-type adult zebrafish liver

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Abstract

Sirtuins (SIRTs) are NAD+-dependent deacetylases that catalyze the hydrolysis of acetyl-lysine residues. They play an important role in many physiological and pathophysiological processes, such as the regulation of lifespan and the prevention of metabolic diseases. In this study, we analyzed the effect of resveratrol on the gene expression levels of SIRT1, SIRT3, SIRT4, PGC1α, and NAMPT, as well as its effect on NAD+ and NADH levels, in the liver of non stressed or non impaired wild-type zebrafish. Semiquantative RT-PCR assays showed that resveratrol did not change the mRNA levels of SIRT1 and PGC1α but decreased the expression levels of the SIRT3, SIRT4, and NAMPT genes. The decrease in NAMPT mRNA levels was accompanied by an increase in NADH levels, thereby decreasing the NAD+/H ratio. Taken together, our results suggest that resveratrol plays a modulatory role in the transcription of the NAMPT, SIRT3, and SIRT4 genes. Zebrafish is an interesting tool that can be used to understand the mechanisms of SIRTs and NAMPT metabolism and to help develop therapeutic compounds. However, further investigations using healthy experimental animals are required to study the modulation of the SIRT and NAMPT genes by resveratrol before it is used as a nutraceutical compound in healthy humans.

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References

  1. Harikumar KB, Aggarwal BB (2008) Resveratrol: a multitargeted agent for age-associated chronic diseases. Cell Cycle 7(8):1020–1035

    Article  PubMed  CAS  Google Scholar 

  2. Howitz KT et al (2003) Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425(6954):191–196

    Article  PubMed  CAS  Google Scholar 

  3. Wood JG et al (2004) Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 430(7000):686–689

    Article  PubMed  CAS  Google Scholar 

  4. Valenzano DR et al (2006) Resveratrol prolongs lifespan and retards the onset of age-related markers in a short-lived vertebrate. Curr Biol 16(3):296–300

    Article  PubMed  CAS  Google Scholar 

  5. Jang M et al (1997) Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 275(5297):218–220

    Article  PubMed  CAS  Google Scholar 

  6. Yar AS et al (2010) The effects of resveratrol on cyclooxygenase-1 and cyclooxygenase-2 mRNA and protein levels in diabetic rat kidneys. Mol Biol Rep 37(5):2323–2331

    Article  PubMed  CAS  Google Scholar 

  7. Marques FZ, Markus MA, Morris BJ (2009) Resveratrol: cellular actions of a potent natural chemical that confers a diversity of health benefits. Int J Biochem Cell Biol 41(11):2125–2128

    Article  PubMed  CAS  Google Scholar 

  8. Szkudelska K, Szkudelski T (2010) Resveratrol, obesity and diabetes. Eur J Pharmacol 635:1–8

    Google Scholar 

  9. Patel KR et al (2010) Clinical pharmacology of resveratrol and its metabolites in colorectal cancer patients. Cancer Res 70(19):7392–7399

    Article  PubMed  CAS  Google Scholar 

  10. Hsieh TC, Wu JM (2010) Resveratrol: biological and pharmaceutical properties as anticancer molecule. Biofactors 36:360–369

    Google Scholar 

  11. Baur JA (2010) Biochemical effects of SIRT1 activators. Biochim Biophys Acta 1804(8):1626–1634

    PubMed  CAS  Google Scholar 

  12. Nunes T et al (2009) Pharmacokinetics of trans-resveratrol following repeated administration in healthy elderly and young subjects. J Clin Pharmacol 49(12):1477–1482

    Article  PubMed  CAS  Google Scholar 

  13. Almeida L et al (2009) Pharmacokinetic and safety profile of trans-resveratrol in a rising multiple-dose study in healthy volunteers. Mol Nutr Food Res 53(Suppl 1):S7–S15

    Article  PubMed  Google Scholar 

  14. Sauve AA et al (2006) The biochemistry of sirtuins. Annu Rev Biochem 75:435–465

    Article  PubMed  CAS  Google Scholar 

  15. Hernick M, Fierke CA (2005) Zinc hydrolases: the mechanisms of zinc-dependent deacetylases. Arch Biochem Biophys 433(1):71–84

    Article  PubMed  CAS  Google Scholar 

  16. Lin SJ, Defossez PA, Guarente L (2000) Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science 289(5487):2126–2128

    Article  PubMed  CAS  Google Scholar 

  17. Michan S, Sinclair D (2007) Sirtuins in mammals: insights into their biological function. Biochem J 404(1):1–13

    Article  PubMed  CAS  Google Scholar 

  18. Haigis MC, Guarente LP (2006) Mammalian sirtuins—emerging roles in physiology, aging, and calorie restriction. Genes Dev 20(21):2913–2921

    Article  PubMed  CAS  Google Scholar 

  19. Feige JN, Auwerx J (2008) Transcriptional targets of sirtuins in the coordination of mammalian physiology. Curr Opin Cell Biol 20(3):303–309

    Article  PubMed  CAS  Google Scholar 

  20. Shi T et al (2005) SIRT3, a mitochondrial sirtuin deacetylase, regulates mitochondrial function and thermogenesis in brown adipocytes. J Biol Chem 280(14):13560–13567

    Article  PubMed  CAS  Google Scholar 

  21. Haigis MC et al (2006) SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell 126(5):941–954

    Article  PubMed  CAS  Google Scholar 

  22. Palacios OM et al (2009) Diet and exercise signals regulate SIRT3 and activate AMPK and PGC-1alpha in skeletal muscle. Aging 1(9):771–783

    PubMed  CAS  Google Scholar 

  23. Lombard DB et al (2007) Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation. Mol Cell Biol 27(24):8807–8814

    Article  PubMed  CAS  Google Scholar 

  24. Imai S, Guarente L (2010) Ten years of NAD-dependent SIR2 family deacetylases: implications for metabolic diseases. Trends Pharmacol Sci 31(5):212–220

    Article  PubMed  CAS  Google Scholar 

  25. Hallows WC, Lee S, Denu JM (2006) Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases. Proc Natl Acad Sci USA 103(27):10230–10235

    Article  PubMed  CAS  Google Scholar 

  26. Schlicker C et al (2008) Substrates and regulation mechanisms for the human mitochondrial sirtuins Sirt3 and Sirt5. J Mol Biol 382(3):790–801

    Article  PubMed  CAS  Google Scholar 

  27. Sundaresan NR et al (2008) SIRT3 is a stress-responsive deacetylase in cardiomyocytes that protects cells from stress-mediated cell death by deacetylation of Ku70. Mol Cell Biol 28(20):6384–6401

    Article  PubMed  CAS  Google Scholar 

  28. Shulga N, Wilson-Smith R, Pastorino JG (2010) Sirtuin-3 deacetylation of cyclophilin D induces dissociation of hexokinase II from the mitochondria. J Cell Sci 123(Pt 6):894–902

    Article  PubMed  CAS  Google Scholar 

  29. Shi T, Fan GQ, Xiao SD (2010) SIRT3 reduces lipid accumulation via AMPK activation in human hepatic cells. J Dig Dis 11(1):55–62

    Article  PubMed  CAS  Google Scholar 

  30. Ahn BH et al (2008) A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis. Proc Natl Acad Sci USA 105(38):14447–14452

    Article  PubMed  CAS  Google Scholar 

  31. Ahuja N et al (2007) Regulation of insulin secretion by SIRT4, a mitochondrial ADP-ribosyltransferase. J Biol Chem 282(46):33583–33592

    Article  PubMed  CAS  Google Scholar 

  32. Stanley CA (2004) Hyperinsulinism/hyperammonemia syndrome: insights into the regulatory role of glutamate dehydrogenase in ammonia metabolism. Mol Genet Metab 81(Suppl 1):S45–S51

    Article  PubMed  CAS  Google Scholar 

  33. Nasrin N et al (2010) SIRT4 regulates fatty acid oxidation and mitochondrial gene expression in liver and muscle cells. J Biol Chem 285:31995–32002

    Google Scholar 

  34. Samal B et al (1994) Cloning and characterization of the cDNA encoding a novel human pre-B-cell colony-enhancing factor. Mol Cell Biol 14(2):1431–1437

    PubMed  CAS  Google Scholar 

  35. Revollo JR et al (2007) Nampt/PBEF/Visfatin regulates insulin secretion in beta cells as a systemic NAD biosynthetic enzyme. Cell Metab 6(5):363–375

    Article  PubMed  CAS  Google Scholar 

  36. Yang H et al (2007) Nutrient-sensitive mitochondrial NAD+ levels dictate cell survival. Cell 130(6):1095–1107

    Article  PubMed  CAS  Google Scholar 

  37. Mukherjee S et al (2009) Expression of the longevity proteins by both red and white wines and their cardioprotective components, resveratrol, tyrosol, and hydroxytyrosol. Free Radic Biol Med 46(5):573–578

    Article  PubMed  CAS  Google Scholar 

  38. Hayashida S et al (2010) Fasting promotes the expression of SIRT1, an NAD+ -dependent protein deacetylase, via activation of PPARalpha in mice. Mol Cell Biochem 339(1–2):285–292

    Article  PubMed  CAS  Google Scholar 

  39. Imai S, Kiess W (2009) Therapeutic potential of SIRT1 and NAMPT-mediated NAD biosynthesis in type 2 diabetes. Front Biosci 14:2983–2995

    Article  PubMed  CAS  Google Scholar 

  40. Zon LI, Peterson RT (2005) In vivo drug discovery in the zebrafish. Nat Rev Drug Discov 4(1):35–44

    Article  PubMed  CAS  Google Scholar 

  41. Pichler FB et al (2003) Chemical discovery and global gene expression analysis in zebrafish. Nat Biotechnol 21(8):879–883

    Article  PubMed  CAS  Google Scholar 

  42. Barbazuk WB et al (2000) The syntenic relationship of the zebrafish and human genomes. Genome Res 10(9):1351–1358

    Article  PubMed  CAS  Google Scholar 

  43. Souto AA et al (2001) Determination of trans-resveratrol concentrations in Brazilian Red Wines by HPLC. J Food Compos Anal 14:441–445

    Article  CAS  Google Scholar 

  44. Chen WY et al (2004) Expression of metallothionein gene during embryonic and early larval development in zebrafish. Aquat Toxicol 69(3):215–227

    Article  PubMed  CAS  Google Scholar 

  45. Kong X et al (2010) Sirtuin 3, a new target of PGC-1alpha, plays an important role in the suppression of ROS and mitochondrial biogenesis. PLoS One 5(7):e11707

    Article  PubMed  Google Scholar 

  46. Bowman TV, Zon LI (2010) Swimming into the future of drug discovery: in vivo chemical screens in zebrafish. ACS Chem Biol 5(2):159–161

    Article  PubMed  CAS  Google Scholar 

  47. Rosemberg DB et al (2010) Taurine prevents enhancement of acetylcholinesterase activity induced by acute ethanol exposure and decreases the level of markers of oxidative stress in zebrafish brain. Neuroscience 171(3):683–692

    Article  PubMed  CAS  Google Scholar 

  48. Pereira TC et al (2011) Zebrafish as a model organism to evaluate drugs potentially able to modulate sirtuin expression. Zebrafish 8(1):9–16

    Article  PubMed  CAS  Google Scholar 

  49. Baur JA et al (2006) Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444(7117):337–342

    Article  PubMed  CAS  Google Scholar 

  50. Lagouge M et al (2006) Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell 127(6):1109–1122

    Article  PubMed  CAS  Google Scholar 

  51. Franco JG et al (2010) Resveratrol (RSV) reduces lipid peroxidation and increases sirtuin1 (SIRT1) expression in adult animals programmed by neonatal protein restriction. J Endocrinol 207(3):319–328

    Article  PubMed  CAS  Google Scholar 

  52. Barger JL et al (2008) Short-term consumption of a resveratrol-containing nutraceutical mixture mimics gene expression of long-term caloric restriction in mouse heart. Exp Gerontol 43(9):859–866

    Article  PubMed  CAS  Google Scholar 

  53. Beher D et al (2009) Resveratrol is not a direct activator of SIRT1 enzyme activity. Chem Biol Drug Des 74(6):619–624

    Article  PubMed  CAS  Google Scholar 

  54. Pacholec M et al (2010) SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1. J Biol Chem 285(11):8340–8351

    Article  PubMed  CAS  Google Scholar 

  55. Barger JL et al (2008) A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice. PLoS One 3(6):e2264

    Article  PubMed  Google Scholar 

  56. Chen D et al (2008) Tissue-specific regulation of SIRT1 by calorie restriction. Genes Dev 22(13):1753–1757

    Article  PubMed  CAS  Google Scholar 

  57. Oliva J et al (2008) Sirt1 is involved in energy metabolism: the role of chronic ethanol feeding and resveratrol. Exp Mol Pathol 85(3):155–159

    Article  PubMed  CAS  Google Scholar 

  58. Rayalam S et al (2008) Resveratrol induces apoptosis and inhibits adipogenesis in 3T3–L1 adipocytes. Phytother Res 22(10):1367–1371

    Article  PubMed  CAS  Google Scholar 

  59. Hirschey MD et al (2010) SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 464(7285):121–125

    Article  PubMed  CAS  Google Scholar 

  60. Chen YR et al (2010) Calorie restriction on insulin resistance and expression of SIRT1 and SIRT4 in rats. Biochem Cell Biol 88(4):715–722

    Article  PubMed  CAS  Google Scholar 

  61. Zhang HS et al (2010) Nicotinamide phosphoribosyltransferase/sirtuin 1 pathway is involved in human immunodeficiency virus type 1 Tat-mediated long terminal repeat transactivation. J Cell Biochem 110(6):1464–1470

    Article  PubMed  CAS  Google Scholar 

  62. Kelly G (2010) A review of the sirtuin system, its clinical implications, and the potential role of dietary activators like resveratrol: part 1. Altern Med Rev 15(3):245–263

    PubMed  Google Scholar 

  63. Dahl TB et al (2007) Increased expression of visfatin in macrophages of human unstable carotid and coronary atherosclerosis: possible role in inflammation and plaque destabilization. Circulation 115(8):972–980

    Article  PubMed  CAS  Google Scholar 

  64. Rasouli N, Kern PA (2008) Adipocytokines and the metabolic complications of obesity. J Clin Endocrinol Metab 93(11 Suppl 1):S64–S73

    Article  PubMed  CAS  Google Scholar 

  65. Sommer G et al (2008) Visfatin/PBEF/Nampt: structure, regulation and potential function of a novel adipokine. Clin Sci 115(1):13–23

    Article  PubMed  CAS  Google Scholar 

  66. Dahl TB et al (2010) Intracellular nicotinamide phosphoribosyltransferase protects against hepatocyte apoptosis and is down-regulated in nonalcoholic fatty liver disease. J Clin Endocrinol Metab 95(6):3039–3047

    Article  PubMed  CAS  Google Scholar 

  67. de Boer JF et al (2009) Plasma levels of PBEF/Nampt/visfatin are decreased in patients with liver cirrhosis. Am J Physiol Gastrointest Liver Physiol 296(2):G196–G201

    Article  PubMed  Google Scholar 

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Acknowledgments

This work was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). The authors would like to thank lab colleagues for technical assistance.

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Correspondence to André Arigony Souto.

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Schirmer, H., Pereira, T.C.B., Rico, E.P. et al. Modulatory effect of resveratrol on SIRT1, SIRT3, SIRT4, PGC1α and NAMPT gene expression profiles in wild-type adult zebrafish liver. Mol Biol Rep 39, 3281–3289 (2012). https://doi.org/10.1007/s11033-011-1096-4

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