Advertisement

Molecular Biology Reports

, Volume 39, Issue 3, pp 3281–3289 | Cite as

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

  • Helena Schirmer
  • Talita Carneiro Brandão Pereira
  • Eduardo Pacheco Rico
  • Denis Broock Rosemberg
  • Carla Denise Bonan
  • Maurício Reis Bogo
  • André Arigony Souto
Article
First Online:
Received:
Accepted:

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.

Keywords

Resveratrol Sirtuins Pgc1 alpha NAMPT Liver 
This is a preview of subscription content, log in to check access.

Notes

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.

References

  1. 1.
    Harikumar KB, Aggarwal BB (2008) Resveratrol: a multitargeted agent for age-associated chronic diseases. Cell Cycle 7(8):1020–1035PubMedCrossRefGoogle Scholar
  2. 2.
    Howitz KT et al (2003) Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425(6954):191–196PubMedCrossRefGoogle Scholar
  3. 3.
    Wood JG et al (2004) Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 430(7000):686–689PubMedCrossRefGoogle Scholar
  4. 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):296–300PubMedCrossRefGoogle Scholar
  5. 5.
    Jang M et al (1997) Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 275(5297):218–220PubMedCrossRefGoogle Scholar
  6. 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):2323–2331PubMedCrossRefGoogle Scholar
  7. 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):2125–2128PubMedCrossRefGoogle Scholar
  8. 8.
    Szkudelska K, Szkudelski T (2010) Resveratrol, obesity and diabetes. Eur J Pharmacol 635:1–8Google Scholar
  9. 9.
    Patel KR et al (2010) Clinical pharmacology of resveratrol and its metabolites in colorectal cancer patients. Cancer Res 70(19):7392–7399PubMedCrossRefGoogle Scholar
  10. 10.
    Hsieh TC, Wu JM (2010) Resveratrol: biological and pharmaceutical properties as anticancer molecule. Biofactors 36:360–369Google Scholar
  11. 11.
    Baur JA (2010) Biochemical effects of SIRT1 activators. Biochim Biophys Acta 1804(8):1626–1634PubMedGoogle Scholar
  12. 12.
    Nunes T et al (2009) Pharmacokinetics of trans-resveratrol following repeated administration in healthy elderly and young subjects. J Clin Pharmacol 49(12):1477–1482PubMedCrossRefGoogle Scholar
  13. 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–S15PubMedCrossRefGoogle Scholar
  14. 14.
    Sauve AA et al (2006) The biochemistry of sirtuins. Annu Rev Biochem 75:435–465PubMedCrossRefGoogle Scholar
  15. 15.
    Hernick M, Fierke CA (2005) Zinc hydrolases: the mechanisms of zinc-dependent deacetylases. Arch Biochem Biophys 433(1):71–84PubMedCrossRefGoogle Scholar
  16. 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):2126–2128PubMedCrossRefGoogle Scholar
  17. 17.
    Michan S, Sinclair D (2007) Sirtuins in mammals: insights into their biological function. Biochem J 404(1):1–13PubMedCrossRefGoogle Scholar
  18. 18.
    Haigis MC, Guarente LP (2006) Mammalian sirtuins—emerging roles in physiology, aging, and calorie restriction. Genes Dev 20(21):2913–2921PubMedCrossRefGoogle Scholar
  19. 19.
    Feige JN, Auwerx J (2008) Transcriptional targets of sirtuins in the coordination of mammalian physiology. Curr Opin Cell Biol 20(3):303–309PubMedCrossRefGoogle Scholar
  20. 20.
    Shi T et al (2005) SIRT3, a mitochondrial sirtuin deacetylase, regulates mitochondrial function and thermogenesis in brown adipocytes. J Biol Chem 280(14):13560–13567PubMedCrossRefGoogle Scholar
  21. 21.
    Haigis MC et al (2006) SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell 126(5):941–954PubMedCrossRefGoogle Scholar
  22. 22.
    Palacios OM et al (2009) Diet and exercise signals regulate SIRT3 and activate AMPK and PGC-1alpha in skeletal muscle. Aging 1(9):771–783PubMedGoogle Scholar
  23. 23.
    Lombard DB et al (2007) Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation. Mol Cell Biol 27(24):8807–8814PubMedCrossRefGoogle Scholar
  24. 24.
    Imai S, Guarente L (2010) Ten years of NAD-dependent SIR2 family deacetylases: implications for metabolic diseases. Trends Pharmacol Sci 31(5):212–220PubMedCrossRefGoogle Scholar
  25. 25.
    Hallows WC, Lee S, Denu JM (2006) Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases. Proc Natl Acad Sci USA 103(27):10230–10235PubMedCrossRefGoogle Scholar
  26. 26.
    Schlicker C et al (2008) Substrates and regulation mechanisms for the human mitochondrial sirtuins Sirt3 and Sirt5. J Mol Biol 382(3):790–801PubMedCrossRefGoogle Scholar
  27. 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):6384–6401PubMedCrossRefGoogle Scholar
  28. 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):894–902PubMedCrossRefGoogle Scholar
  29. 29.
    Shi T, Fan GQ, Xiao SD (2010) SIRT3 reduces lipid accumulation via AMPK activation in human hepatic cells. J Dig Dis 11(1):55–62PubMedCrossRefGoogle Scholar
  30. 30.
    Ahn BH et al (2008) A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis. Proc Natl Acad Sci USA 105(38):14447–14452PubMedCrossRefGoogle Scholar
  31. 31.
    Ahuja N et al (2007) Regulation of insulin secretion by SIRT4, a mitochondrial ADP-ribosyltransferase. J Biol Chem 282(46):33583–33592PubMedCrossRefGoogle Scholar
  32. 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–S51PubMedCrossRefGoogle Scholar
  33. 33.
    Nasrin N et al (2010) SIRT4 regulates fatty acid oxidation and mitochondrial gene expression in liver and muscle cells. J Biol Chem 285:31995–32002Google Scholar
  34. 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):1431–1437PubMedGoogle Scholar
  35. 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):363–375PubMedCrossRefGoogle Scholar
  36. 36.
    Yang H et al (2007) Nutrient-sensitive mitochondrial NAD+ levels dictate cell survival. Cell 130(6):1095–1107PubMedCrossRefGoogle Scholar
  37. 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):573–578PubMedCrossRefGoogle Scholar
  38. 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):285–292PubMedCrossRefGoogle Scholar
  39. 39.
    Imai S, Kiess W (2009) Therapeutic potential of SIRT1 and NAMPT-mediated NAD biosynthesis in type 2 diabetes. Front Biosci 14:2983–2995PubMedCrossRefGoogle Scholar
  40. 40.
    Zon LI, Peterson RT (2005) In vivo drug discovery in the zebrafish. Nat Rev Drug Discov 4(1):35–44PubMedCrossRefGoogle Scholar
  41. 41.
    Pichler FB et al (2003) Chemical discovery and global gene expression analysis in zebrafish. Nat Biotechnol 21(8):879–883PubMedCrossRefGoogle Scholar
  42. 42.
    Barbazuk WB et al (2000) The syntenic relationship of the zebrafish and human genomes. Genome Res 10(9):1351–1358PubMedCrossRefGoogle Scholar
  43. 43.
    Souto AA et al (2001) Determination of trans-resveratrol concentrations in Brazilian Red Wines by HPLC. J Food Compos Anal 14:441–445CrossRefGoogle Scholar
  44. 44.
    Chen WY et al (2004) Expression of metallothionein gene during embryonic and early larval development in zebrafish. Aquat Toxicol 69(3):215–227PubMedCrossRefGoogle Scholar
  45. 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):e11707PubMedCrossRefGoogle Scholar
  46. 46.
    Bowman TV, Zon LI (2010) Swimming into the future of drug discovery: in vivo chemical screens in zebrafish. ACS Chem Biol 5(2):159–161PubMedCrossRefGoogle Scholar
  47. 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):683–692PubMedCrossRefGoogle Scholar
  48. 48.
    Pereira TC et al (2011) Zebrafish as a model organism to evaluate drugs potentially able to modulate sirtuin expression. Zebrafish 8(1):9–16PubMedCrossRefGoogle Scholar
  49. 49.
    Baur JA et al (2006) Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444(7117):337–342PubMedCrossRefGoogle Scholar
  50. 50.
    Lagouge M et al (2006) Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell 127(6):1109–1122PubMedCrossRefGoogle Scholar
  51. 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):319–328PubMedCrossRefGoogle Scholar
  52. 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):859–866PubMedCrossRefGoogle Scholar
  53. 53.
    Beher D et al (2009) Resveratrol is not a direct activator of SIRT1 enzyme activity. Chem Biol Drug Des 74(6):619–624PubMedCrossRefGoogle Scholar
  54. 54.
    Pacholec M et al (2010) SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1. J Biol Chem 285(11):8340–8351PubMedCrossRefGoogle Scholar
  55. 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):e2264PubMedCrossRefGoogle Scholar
  56. 56.
    Chen D et al (2008) Tissue-specific regulation of SIRT1 by calorie restriction. Genes Dev 22(13):1753–1757PubMedCrossRefGoogle Scholar
  57. 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):155–159PubMedCrossRefGoogle Scholar
  58. 58.
    Rayalam S et al (2008) Resveratrol induces apoptosis and inhibits adipogenesis in 3T3–L1 adipocytes. Phytother Res 22(10):1367–1371PubMedCrossRefGoogle Scholar
  59. 59.
    Hirschey MD et al (2010) SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 464(7285):121–125PubMedCrossRefGoogle Scholar
  60. 60.
    Chen YR et al (2010) Calorie restriction on insulin resistance and expression of SIRT1 and SIRT4 in rats. Biochem Cell Biol 88(4):715–722PubMedCrossRefGoogle Scholar
  61. 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):1464–1470PubMedCrossRefGoogle Scholar
  62. 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):245–263PubMedGoogle Scholar
  63. 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):972–980PubMedCrossRefGoogle Scholar
  64. 64.
    Rasouli N, Kern PA (2008) Adipocytokines and the metabolic complications of obesity. J Clin Endocrinol Metab 93(11 Suppl 1):S64–S73PubMedCrossRefGoogle Scholar
  65. 65.
    Sommer G et al (2008) Visfatin/PBEF/Nampt: structure, regulation and potential function of a novel adipokine. Clin Sci 115(1):13–23PubMedCrossRefGoogle Scholar
  66. 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):3039–3047PubMedCrossRefGoogle Scholar
  67. 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–G201PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  • Helena Schirmer
    • 1
    • 2
  • Talita Carneiro Brandão Pereira
    • 3
  • Eduardo Pacheco Rico
    • 4
  • Denis Broock Rosemberg
    • 4
  • Carla Denise Bonan
    • 5
  • Maurício Reis Bogo
    • 3
  • André Arigony Souto
    • 1
  1. 1.Laboratório de Química de Produtos Naturais, Departamento de Química Pura, Faculdade de QuímicaPontifícia Universidade Católica do Rio Grande do SulPorto AlegreBrazil
  2. 2.Laboratório de BiomedicinaUniversidade FeevaleNovo HamburgoBrazil
  3. 3.Laboratório de Biologia Genômica e Molecular, Departamento de Biologia Celular e Molecular, Faculdade de BiociênciasPontifícia Universidade Católica do Rio Grande do SulPorto AlegreBrazil
  4. 4.Departamento de Bioquímica, Instituto de Ciências Básicas da SaúdeUniversidade Federal do Rio Grande do SulPorto AlegreBrazil
  5. 5.Laboratório de Neuroquímica e Psicofarmacologia, Departamento de Biologia Celular e Molecular, Faculdade de BiociênciasPontifícia Universidade Católica do Rio Grande do SulPorto AlegreBrazil

Personalised recommendations

Cite article

Buy options