Skip to main content

Advertisement

SpringerLink
Log in

Nicotinamide is an inhibitor of SIRT1 in vitro, but can be a stimulator in cells

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Nicotinamide (NAM), a form of vitamin B3, plays essential roles in cell physiology through facilitating NAD+ redox homeostasis and providing NAD+ as a substrate to a class of enzymes that catalyze non-redox reactions. These non-redox enzymes include the sirtuin family proteins which deacetylate target proteins while cleaving NAD+ to yield NAM. Since the finding that NAM exerts feedback inhibition to the sirtuin reactions, NAM has been widely used as an inhibitor in the studies where SIRT1, a key member of sirtuins, may have a role in certain cell physiology. However, once administered to cells, NAM is rapidly converted to NAD+ and, therefore, the cellular concentration of NAM decreases rapidly while that of NAD+ increases. The result would be an inhibition of SIRT1 for a limited duration, followed by an increase in the activity. This possibility raises a concern on the validity of the interpretation of the results in the studies that use NAM as a SIRT1 inhibitor. To understand better the effects of cellular administration of NAM, we reviewed published literature in which treatment with NAM was used to inhibit SIRT1 and found that the expected inhibitory effect of NAM was either unreliable or muted in many cases. In addition, studies demonstrated NAM administration stimulates SIRT1 activity and improves the functions of cells and organs. To determine if NAM administration can generate conditions in cells and tissues that are stimulatory to SIRT1, the changes in the cellular levels of NAM and NAD+ reported in the literature were examined and the factors that are involved in the availability of NAD+ to SIRT1 were evaluated. We conclude that NAM treatment can hypothetically be stimulatory to SIRT1.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

NAM:

Nicotinamide

NAD+ :

Nicotinamide adenine dinucleotide

NAMPT:

Nicotinamide phosphoribosyltransferase

SIRT1:

Sirtuin 1

PARP:

Poly(ADP-ribose) polymerase

eNAMPT:

Extracellular NAMPT

NMNAT-1:

NMN adenyl transferase

ARTs:

Mono-ADP-ribosyl transferases

2-PY:

N-methyl-2-pyridone-5-carboxamide

4-PY:

N-methyl-4-pyridone-5-carboxamide

References

  1. Oblong JE (2014) The evolving role of the NAD+/nicotinamide metabolome in skin homeostasis, cellular bioenergetics, and aging. DNA Repair (Amst) 23:59–63. doi:10.1016/j.dnarep.2014.04.005

    Article  CAS  Google Scholar 

  2. Stevens MJ, Li F, Drel VR, Abatan OI, Kim H, Burnett D, Larkin D, Obrosova IG (2007) Nicotinamide reverses neurological and neurovascular deficits in streptozotocin diabetic rats. J Pharmacol Exp Ther 320(1):458–464. doi:10.1124/jpet.106.109702

    Article  CAS  PubMed  Google Scholar 

  3. Santidrian AF, LeBoeuf SE, Wold ED, Ritland M, Forsyth JS, Felding BH (2014) Nicotinamide phosphoribosyltransferase can affect metastatic activity and cell adhesive functions by regulating integrins in breast cancer. DNA Repair (Amst) 23:79–87. doi:10.1016/j.dnarep.2014.08.006

    Article  CAS  Google Scholar 

  4. Lee EJ, Wu TS, Chang GL, Li CY, Chen TY, Lee MY, Chen HY, Maynard KI (2006) Delayed treatment with nicotinamide inhibits brain energy depletion, improves cerebral microperfusion, reduces brain infarct volume, but does not alter neurobehavioral outcome following permanent focal cerebral ischemia in Sprague Dawley rats. Curr Neurovasc Res 3(3):203–213. doi:10.2174/1567206778018749

    Article  CAS  PubMed  Google Scholar 

  5. Ayoub IA, Maynard KI (2002) Therapeutic window for nicotinamide following transient focal cerebral ischemia. NeuroReport 13(2):213–216. doi:10.1097/00001756-200202110-00008

    Article  CAS  PubMed  Google Scholar 

  6. Sakakibara Y, Mitha AP, Ogilvy CS, Maynard KI (2000) Post-treatment with nicotinamide (vitamin B(3)) reduces the infarct volume following permanent focal cerebral ischemia in female Sprague-Dawley and Wistar rats. Neurosci Lett 281(2–3):111–114. doi:10.1016/S0304-3940(00)00854-5

    Article  CAS  PubMed  Google Scholar 

  7. Kaneko S, Wang J, Kaneko M, Yiu G, Hurrell JM, Chitnis T, Khoury SJ, He Z (2006) Protecting axonal degeneration by increasing nicotinamide adenine dinucleotide levels in experimental autoimmune encephalomyelitis models. J Neurosci 26(38):9794–9804. doi:10.1523/JNEUROSCI.2116-06.2006

    Article  CAS  PubMed  Google Scholar 

  8. Bayrakdar ET, Armagan G, Uyanikgil Y, Kanit L, Koylu E, Yalcin A (2014) Ex vivo protective effects of nicotinamide and 3-aminobenzamide on rat synaptosomes treated with Abeta(1-42). Cell Biochem Funct 32(7):557–564. doi:10.1002/cbf.3049

    Article  PubMed  CAS  Google Scholar 

  9. Murray MF (2003) Nicotinamide: an oral antimicrobial agent with activity against both Mycobacterium tuberculosis and human immunodeficiency virus. Clin Infect Dis 36(4):453–460. doi:10.1086/367544

    Article  CAS  PubMed  Google Scholar 

  10. Maiese K, Chong ZZ, Hou J, Shang YC (2009) The vitamin nicotinamide: translating nutrition into clinical care. Molecules 14(9):3446–3485. doi:10.3390/molecules14093446

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Chaffin WL, Barton RA, Jacobson EL, Jacobson MK (1979) Nicotinamide adenine dinucleotide metabolism in Candida albicans. J Bacteriol 139(3):883–888

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Revollo JR, Grimm AA, Imai S (2004) The NAD biosynthesis pathway mediated by nicotinamide phosphoribosyltransferase regulates Sir2 activity in mammalian cells. J Biol Chem 279(49):50754–50763. doi:10.1074/jbc.M408388200

    Article  CAS  PubMed  Google Scholar 

  13. Hasmann M, Schemainda I (2003) FK866, a highly specific noncompetitive inhibitor of nicotinamide phosphoribosyltransferase, represents a novel mechanism for induction of tumor cell apoptosis. Cancer Res 63(21):7436–7442

    CAS  PubMed  Google Scholar 

  14. Hayaishi O, Ueda K (1977) Poly(ADP-ribose) and ADP-ribosylation of proteins. Annu Rev Biochem 46:95–116. doi:10.1146/annurev.bi.46.070177.000523

    Article  CAS  PubMed  Google Scholar 

  15. Bitterman KJ, Anderson RM, Cohen HY, Latorre-Esteves M, Sinclair DA (2002) Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast sir2 and human SIRT1. J Biol Chem 277(47):45099–45107. doi:10.1074/jbc.M205670200

    Article  CAS  PubMed  Google Scholar 

  16. Zhao K, Harshaw R, Chai X, Marmorstein R (2004) Structural basis for nicotinamide cleavage and ADP-ribose transfer by NAD(+)-dependent Sir2 histone/protein deacetylases. Proc Natl Acad Sci USA 101(23):8563–8568. doi:10.1073/pnas.0401057101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. North BJ, Verdin E (2004) Sirtuins: Sir2-related NAD-dependent protein deacetylases. Genome Biol 5(5):224. doi:10.1186/gb-2004-5-5-224

    Article  PubMed  PubMed Central  Google Scholar 

  18. Imai S, Guarente L (2014) NAD+ and sirtuins in aging and disease. Trends Cell Biol 24(8):464–471. doi:10.1016/j.tcb.2014.04.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Avalos JL, Bever KM, Wolberger C (2005) Mechanism of sirtuin inhibition by nicotinamide: altering the NAD(+) cosubstrate specificity of a Sir2 enzyme. Mol Cell 17(6):855–868. doi:10.1016/j.molcel.2005.02.022

    Article  CAS  PubMed  Google Scholar 

  20. Schmidt MT, Smith BC, Jackson MD, Denu JM (2004) Coenzyme specificity of Sir2 protein deacetylases: implications for physiological regulation. J Biol Chem 279(38):40122–40129. doi:10.1074/jbc.M407484200

    Article  CAS  PubMed  Google Scholar 

  21. Sauve AA, Schramm VL (2003) Sir2 regulation by nicotinamide results from switching between base exchange and deacetylation chemistry. Biochemistry 42(31):9249–9256. doi:10.1021/bi034959l

    Article  CAS  PubMed  Google Scholar 

  22. Jackson MD, Schmidt MT, Oppenheimer NJ, Denu JM (2003) Mechanism of nicotinamide inhibition and transglycosidation by Sir2 histone/protein deacetylases. J Biol Chem 278(51):50985–50998. doi:10.1074/jbc.M306552200

    Article  CAS  PubMed  Google Scholar 

  23. Ghislain M, Talla E, Francois JM (2002) Identification and functional analysis of the Saccharomyces cerevisiae nicotinamidase gene, PNC1. Yeast 19(3):215–224. doi:10.1002/yea.810

    Article  CAS  PubMed  Google Scholar 

  24. Anderson RM, Bitterman KJ, Wood JG, Medvedik O, Sinclair DA (2003) Nicotinamide and PNC1 govern lifespan extension by calorie restriction in Saccharomyces cerevisiae. Nature 423(6936):181–185. doi:10.1038/nature01578

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Gallo CM, Smith DL Jr, Smith JS (2004) Nicotinamide clearance by Pnc1 directly regulates Sir2-mediated silencing and longevity. Mol Cell Biol 24(3):1301–1312. doi:10.1128/MCB.24.3.1301-1312.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Sandmeier JJ, Celic I, Boeke JD, Smith JS (2002) Telomeric and rDNA silencing in Saccharomyces cerevisiae are dependent on a nuclear NAD(+) salvage pathway. Genetics 160(3):877–889

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Feldman JL, Dittenhafer-Reed KE, Kudo N, Thelen JN, Ito A, Yoshida M, Denu JM (2015) Kinetic and structural basis for acyl-group selectivity and NAD(+) dependence in sirtuin-catalyzed deacylation. Biochemistry 54(19):3037–3050. doi:10.1021/acs.biochem.5b00150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Yang H, Lavu S, Sinclair DA (2006) Nampt/PBEF/Visfatin: a regulator of mammalian health and longevity? Exp Gerontol 41(8):718–726. doi:10.1016/j.exqer.2006.06.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Rye PT, Frick LE, Ozbal CC, Lamarr WA (2011) Advances in label-free screening approaches for studying histone acetyltransferases. J Biomol Screen 16(10):1186–1195. doi:10.1177/1087057111418653

    Article  CAS  PubMed  Google Scholar 

  30. Guan X, Lin P, Knoll E, Chakrabarti R (2014) Mechanism of inhibition of the human sirtuin enzyme SIRT3 by nicotinamide: computational and experimental studies. PLoS One 9(9):e107729. doi:10.1371/journal.pone.0107729

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Madsen AS, Andersen C, Daoud M et al (2016) Investigating the sensitivity of NAD+-dependent sirtuin deacylation activities to NADH. J Biol Chem 291(13):7128–7141. doi:10.1074/jbc.M115.668699

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Fu Y, Wang Y, Du L, Xu C, Cao J, Fan T, Liu J, Su X, Fan S, Liu Q, Fan F (2013) Resveratrol inhibits ionising irradiation-induced inflammation in MSCs by activating SIRT1 and limiting NLRP-3 inflammasome activation. Int J Mol Sci 14(7):14105–14118. doi:10.3390/ijms140714105

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Schroder K, Tschopp J (2010) The inflammasomes. Cell 140(6):821–832. doi:10.1016/j.cell.2010.01.040

    Article  CAS  PubMed  Google Scholar 

  34. Chen ML, Yi L, Jin X et al (2013) Resveratrol attenuates vascular endothelial inflammation by inducing autophagy through the cAMP signaling pathway. Autophagy 9(12):2033–2045. doi:10.4161/auto.26336

    Article  CAS  PubMed  Google Scholar 

  35. Jang SY, Kang HT, Hwang ES (2012) Nicotinamide-induced mitophagy: event mediated by high NAD+/NADH ratio and SIRT1 protein activation. J Biol Chem 287(23):19304–19314. doi:10.1074/jbc.M112.363747

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lee IH, Cao L, Mostoslavsky R, Lombard DB, Liu J, Bruns NE, Tsokos M, Alt FW, Finkel T (2008) A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Proc Natl Acad Sci USA 105(9):3374–3379. doi:10.1073/pnas.0712145105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Huang R, Xu Y, Wan W et al (2015) Deacetylation of nuclear LC3 drives autophagy initiation under starvation. Mol Cell 57(3):456–466. doi:10.1016/j.molcel.2014.12.013

    Article  CAS  PubMed  Google Scholar 

  38. Kang HT, Hwang ES (2009) Nicotinamide enhances mitochondria quality through autophagy activation in human cells. Aging Cell 8(4):426–438. doi:10.1111/j.1474-9726.2009.00487.x

    Article  CAS  PubMed  Google Scholar 

  39. Choi HJ, Jang SY, Hwang ES (2015) High-dose nicotinamide suppresses ROS generation and augments population expansion during CD8(+) T cell activation. Mol Cells 38(10):918–924. doi:10.14348/molcells.2015.0168

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Santidrian AF, Matsuno-Yagi A, Ritland M et al (2013) Mitochondrial complex I activity and NAD+/NADH balance regulate breast cancer progression. J Clin Invest 123(3):1068–1081. doi:10.1172/JCI64264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Li J, Dou X, Li S, Zhang X, Zeng Y (1853) Song Z (2015) Nicotinamide ameliorates palmitate-induced ER stress in hepatocytes via cAMP/PKA/CREB pathway-dependent Sirt1 upregulation. Biochim Biophys Acta 11 Pt A:2929–2936. doi:10.1016/j.bbamcr.2015.09.003

    Google Scholar 

  42. Gerhart-Hines Z, Dominy JE Jr, Blattler SM, Jedrychowski MP, Banks AS, Lim JH, Chim H, Gygi SP, Puigserver P (2011) The cAMP/PKA pathway rapidly activates SIRT1 to promote fatty acid oxidation independently of changes in NAD(+). Mol Cell 44(6):851–863. doi:10.1016/j.molcel.2011.12.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kaplan NO, Goldin A, Humphreys SR, Ciotti MM, Stolzenbach FE (1956) Pyridine nucleotide synthesis in the mouse. J Biol Chem 219(1):287–298

    CAS  PubMed  Google Scholar 

  44. Clark JB, Pinder S (1969) Control of the steady-state concentrations of the nicotinamide nucleotides in rat liver. Biochem J 114(2):321–330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Greengard P, Quinn GP, Reid MB (1964) Pituitary influence of pyridine nucleotide metabolism of rat liver. J Biol Chem 239:1887–1892

    CAS  PubMed  Google Scholar 

  46. Lee HI, Jang SY, Kang HT, Hwang ES (2008) p53-, SIRT1-, and PARP-1-independent downregulation of p21WAF1 expression in nicotinamide-treated cells. Biochem Biophys Res Commun 368(2):298–304. doi:10.1016/j.bbrc.2008.01.082

    Article  CAS  PubMed  Google Scholar 

  47. Yang H, Yang T, Baur JA et al (2007) Nutrient-sensitive mitochondrial NAD+ levels dictate cell survival. Cell 130(6):1095–1107. doi:10.1016/j.cell.2007.07.035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Yamada K, Hara N, Shibata T, Osago H, Tsuchiya M (2006) The simultaneous measurement of nicotinamide adenine dinucleotide and related compounds by liquid chromatography/electrospray ionization tandem mass spectrometry. Anal Biochem 352(2):282–285. doi:10.1016/j.ab.2006.02.017

    Article  CAS  PubMed  Google Scholar 

  49. Hara N, Yamada K, Shibata T, Osago H, Hashimoto T, Tsuchiya M (2007) Elevation of cellular NAD levels by nicotinic acid and involvement of nicotinic acid phosphoribosyltransferase in human cells. J Biol Chem 282(34):24574–24582. doi:10.1074/jbc.M610357200

    Article  CAS  PubMed  Google Scholar 

  50. Marcotte PA, Richardson PL, Guo J, Barrett LW, Xu N, Gunasekera A, Glaser KB (2004) Fluorescence assay of SIRT protein deacetylases using an acetylated peptide substrate and a secondary trypsin reaction. Anal Biochem 332(1):90–99. doi:10.1016/j.ab.2004.05.039

    Article  CAS  PubMed  Google Scholar 

  51. Smith BC, Denu JM (2009) Chemical mechanisms of histone lysine and arginine modifications. Biochim Biophys Acta 1789(1):45–57. doi:10.1016/j.bbagrm.2008.06.005

    Article  CAS  PubMed  Google Scholar 

  52. Collins PB, Chaykin S (1972) The management of nicotinamide and nicotinic acid in the mouse. J Biol Chem 247(3):778–783

    CAS  PubMed  Google Scholar 

  53. Trammell SA, Schmidt MS, Weidemann BJ et al (2016) Ncotinamide riboside is uniquely and orally bioavailable in mice and humans. Nat Commun 7:12948. doi:10.1038/ncomms12948

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Langan TA Jr, Kaplan NO, Shuster L (1959) Formation of the nicotinic acid analogue of diphosphopyridine nucleotide after nicotinamide administration. J Biol Chem 234(8):2161–2168

    CAS  PubMed  Google Scholar 

  55. Yang NC, Song TY, Chang YZ, Chen MY, Hu ML (2015) Up-regulation of nicotinamide phosphoribosyltransferase and increase of NAD+ levels by glucose restriction extend replicative lifespan of human fibroblast Hs68 cells. Biogerontology 16(1):31–42. doi:10.1007/s10522-014-9528-x

    Article  CAS  PubMed  Google Scholar 

  56. Sun Y, Li J, Xiao N, Wang M, Kou J, Qi L, Huang F, Liu B, Liu K (2014) Pharmacological activation of AMPK ameliorates perivascular adipose/endothelial dysfunction in a manner interdependent on AMPK and SIRT1. Pharmacol Res 89:19–28. doi:10.1016/j.phrs.2014.07.006

    Article  CAS  PubMed  Google Scholar 

  57. Zhang T, Zhou Y, Li L, Wang HH, Ma XS, Qian WP, Shen W, Schatten H, Sun QY (2016) SIRT1, 2, 3 protect mouse oocytes from postovulatory aging. Aging (Albany NY) 8(4):685–696. doi:10.18632/aging.100911

    Article  Google Scholar 

  58. Burgos ES, Schramm VL (2008) Weak coupling of ATP hydrolysis to the chemical equilibrium of human nicotinamide phosphoribosyltransferase. Biochemistry 47(42):11086–11096. doi:10.1021/bi801198m

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Shibata K, Murata K, Hayakawa T, Iwai K (1985) Effect of dietary orotic acid on the levels of liver and blood NAD in rats. J Nutr Sci Vitaminol (Tokyo) 31(3):265–278. doi:10.3177/jnsv.31.265

    Article  CAS  Google Scholar 

  60. Hara N, Yamada K, Shibata T, Osago H, Tsuchiya M (2011) Nicotinamide phosphoribosyltransferase/visfatin does not catalyze nicotinamide mononucleotide formation in blood plasma. PLoS One 6(8):e22781. doi:10.1371/journal.pone.0022781

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Peters GJ, Laurensse E, Leyva A, Pinedo HM (1985) The concentration of 5-phosphoribosyl 1-pyrophosphate in monolayer tumor cells and the effect of various pyrimidine antimetabolites. Int J Biochem 17(1):95–99. doi:10.1016/0020-711X(85)90091-6

    Article  CAS  PubMed  Google Scholar 

  62. Fridman A, Saha A, Chan A, Casteel DE, Pilz RB, Boss GR (2013) Cell cycle regulation of purine synthesis by phosphoribosyl pyrophosphate and inorganic phosphate. Biochem J 454(1):91–99. doi:10.1042/BJ20130153

    Article  CAS  PubMed  Google Scholar 

  63. Skaper SD, Willis RC, Seegmiller JE (1976) Intracellular 5-phosphoribosyl-1-pyrophosphate: decreased availability during glutamine limitation. Science 193(4253):587–588. doi:10.1126/science.959817

    Article  CAS  PubMed  Google Scholar 

  64. Revollo JR, Körner A et al (2007) Nampt/PBEF/visfatin regulates insulin secretion in β cells as a systemic NAD biosynthetic enzyme. Cell Metab 6(5):363–375. doi:10.1016/j.cmet.2007.09.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Haider DG, Schaller G, Kapiotis S, Maier C, Luger A (2006) The release of the adipocytokine visfatin is regulated by glucose and insulin. Diabetologia 49:1909–1914. doi:10.1007/s00125-006-0303-7

    Article  CAS  PubMed  Google Scholar 

  66. Tanaka M, Nozaki M, Fukuhara A, Segawa K, Aoki N, Matsuda M, Komuro R, Shimomura I (2007) Visfatin is released from 3T3-L1 adipocytes via a non-classical pathway. Biochem Biophys Res Commun 359(2):194–201. doi:10.1016/j.bbrc.2007.05.096

    Article  CAS  PubMed  Google Scholar 

  67. Garten A, Petzold S, Barnikol-Oettler A, Körner A, Thasler WE, Kratzsch J, Kiess W, Gebhardt R (2010) Nicotinamide phosphoribosyltransferase (NAMPT/PBEF/visfatin) is constitutively released from human hepatocytes. Biochem Biophys Res Commun 391(1):376–381. doi:10.1016/j.bbrc.2009.11.006

    Article  CAS  PubMed  Google Scholar 

  68. Grolla AA, Torretta S, Gnemmi I et al (2015) Nicotinamide phosphoribosyltransferase (NAMPT/PBEF/visfatin) is a tumoural cytokine released from melanoma. Pigment Cell Melanoma Res 28(6):718–729. doi:10.1111/pcmr.12420

    Article  CAS  PubMed  Google Scholar 

  69. Zhang HP, Zou J, Xu ZO, Ruan J, Yang SD, Yin Y, Mu HJ (2017) Association of leptin, visfatin, apelin, resistin and adiponectin with clear cell renal cell carcinoma. Oncol Lett 13:463–468. doi:10.3892/ol.2016.5408

    PubMed  Google Scholar 

  70. Costford SR, Bajpeyi S, Pasarica M et al (2010) Skeletal muscle NAMPT is induced by exercise in humans. Am J Physiol Endocrinol Metab 298(1):E117–E126. doi:10.1152/ajpendo.00318.2009

    Article  CAS  PubMed  Google Scholar 

  71. Kover K, Tong PY, Watkins D et al (2013) Expression and regulation of nampt in human islets. PLoS One 8(3):e58767. doi:10.1371/journal.pone.0058767

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Kim D, Lee G, Huh YH, Lee SY, Park KH, Kim S, Kim J, Koh J, Ryu J (2017) NAMPT Is an Essential Regulator of RA-Mediated Periodontal Inflammation. J Dent Res 1:22034517690389. doi:10.1177/0022034517690389

    Google Scholar 

  73. Yano M, Akazawa H, Oka T, Yabumoto C, Kudo-Sakamoto Y, Kamo T, Shimizu Y, Yagi H, Naito AT, Lee JK, Suzuki J, Sakata Y, Komuro I (2015) Monocyte-derived extracellular Nampt-dependent biosynthesis of NAD(+) protects the heart against pressure overload. Sci Rep 5:15857. doi:10.1038/srep15857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Goodwin PM, Lewis PJ, Davies MI, Skidmore CJ, Shall S (1978) The effect of gamma radiation and neocarzinostatin on NAD and ATP levels in mouse leukaemia cells. Biochim Biophys Acta 543(4):576–582. doi:10.1016/0304-4165(78)90312-4

    Article  CAS  PubMed  Google Scholar 

  75. Skidmore CJ, Davies MI, Goodwin PM, Halldorsson H, Lewis PJ, Shall S, Zia’ee AA (1979) The involvement of poly(ADP-ribose) polymerase in the degradation of NAD caused by gamma-radiation and N-methyl-N-nitrosourea. Eur J Biochem 101(1):135–142. doi:10.1111/j.1432-1033.1979.tb04225.x

    Article  CAS  PubMed  Google Scholar 

  76. Pillai JB, Isbatan A, Imai S, Gupta MP (2005) Poly(ADP-ribose) polymerase-1-dependent cardiac myocyte cell death during heart failure is mediated by NAD+ depletion and reduced Sir2alpha deacetylase activity. J Biol Chem 280(52):43121–43130. doi:10.1074/jbc.M506162200

    Article  CAS  PubMed  Google Scholar 

  77. Bai P, Cantó C, Oudart H et al (2011) PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation. Cell Metab 13(4):461–468. doi:10.1016/j.cmet.2011.03.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Mendoza-Alvarez H, Alvarez-Gonzalez R (1993) Enzymology of ADP-ribose polymer synthesis. J Biol Chem 268(30):22575–22580. doi:10.1007/978-1-4615-2614-8_4

    CAS  PubMed  Google Scholar 

  79. Banasik M, Stedeford T, Strosznajder RP, Persad AS, Tanaka S, Ueda K (2004) The effects of organic solvents on poly(ADP-ribose) polymerase-1 activity: implications for neurotoxicity. Acta Neurobiol Exp (Wars) 64(4):467–473

    Google Scholar 

  80. Shieh WM, Amé JC, Wilson MV, Wang ZQ, Koh DW, Jacobson MK, Jacobson EL (1998) Poly(ADP-ribose) polymerase null mouse cells synthesize ADP-ribose polymers. J Biol Chem 273(46):30069–30072. doi:10.1074/jbc.273.46.30069

    Article  CAS  PubMed  Google Scholar 

  81. Pittelli M, Formentini L, Faraco G et al (2010) Inhibition of nicotinamide phosphoribosyltransferase: cellular bioenergetics reveals a mitochondrial insensitive NAD pool. J Biol Chem 285(44):34106–34114. doi:10.1074/jbc.M110.136739

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Chini EN (2009) CD38 as a regulator of cellular NAD: a novel potential pharmacological target for metabolic conditions. Curr Pharm Des 15(1):57–63. doi:10.2174/138161209787185788

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Malavasi F, Deaglio S, Funaro A, Ferrero E, Horenstein AL, Ortolan E, Vaisitti T, Aydin S (2008) Evolution and function of the ADP ribosyl cyclase/CD38 gene family in physiology and pathology. Physiol Rev 88(3):841–886. doi:10.1152/physrev.00035.2007

    Article  CAS  PubMed  Google Scholar 

  84. Rankin PW, Jacobson EL, Benjamin RC, Moss J, Jacobson MK (1989) Quantitative studies of inhibitors of ADP-ribosylation in vitro and in vivo. J Biol Chem 264(8):4312–4317

    CAS  PubMed  Google Scholar 

  85. Ohashi K, Kawai S, Koshimizu M, Murata K (2011) NADPH regulates human NAD kinase, a NADP+-biosynthetic enzyme. Mol Cell Biochem 355(1–2):57–64. doi:10.1007/s11010-011-0838-x

    Article  CAS  PubMed  Google Scholar 

  86. Cantoni GL (1951) Methylation of nicotinamide with soluble enzyme system from rat liver. J Biol Chem 189(1):203–216

    CAS  PubMed  Google Scholar 

  87. Aksoy S, Szumlanski CL, Weinshilboum RM (1994) Human liver nicotinamide N-methyltransferase. cDNA cloning, expression, and biochemical characterization. J Biol Chem 269(20):14835–14840

    CAS  PubMed  Google Scholar 

  88. Rutkowski B, Slominska E, Szolkiewicz M et al (2003) N-methyl-2-pyridone-5-carboxamide: a novel uremic toxin? Kidney Int Suppl 84:S19–S21. doi:10.1046/j.1523-1755.63.s84.36.x

    Article  CAS  Google Scholar 

  89. Beyer KH, Russo HF et al (1950) Renal tubular elimination of N1-methylnicotinamide. Am J Physiol 160(2):311–320

    CAS  PubMed  Google Scholar 

  90. Marcu R, Wiczer BM, Neeley CK, Hawkins BJ (2014) Mitochondrial matrix Ca2+ accumulation regulates cytosolic NAD+/NADH metabolism, protein acetylation, and sirtuin expression. Mol Cell Biol 34(15):2890–2902. doi:10.1128/MCB.00068-14

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Veech RL (2006) The determination of the redox states and phosphorylation potential in living tissues and their relationship to metabolic control of disease phenotypes. Biochem Mol Biol Educ 34(3):168–179. doi:10.1002/bmb.2006.49403403168

    Article  CAS  PubMed  Google Scholar 

  92. Williamson DH, Lund P, Krebs HA (1967) The redox state of free nicotinamide-adenine dinucleotide in the cytoplasm and mitochondria of rat liver. Biochem J 103(2):514–527. doi:10.1042/bj1030514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Houtkooper RH, Cantó C, Wanders RJ, Auwerx J (2010) The secret life of NAD+: an old metabolite controlling new metabolic signaling pathways. Endocr Rev 31(2):194–223. doi:10.1210/er.2009-0026

    Article  CAS  PubMed  Google Scholar 

  94. Kitani T, Okuno S, Fujisawa H (2003) Growth phase-dependent changes in the subcellular localization of pre-B-cell colony-enhancing factor. FEBS Lett 544(1–3):74–78. doi:10.1016/S0014-5793(03)00476-9

    Article  CAS  PubMed  Google Scholar 

  95. Magni G, Amici A, Emanuelli M, Raffaelli N, Ruggieri S (1999) Enzymology of NAD+ synthesis. Adv Enzymol Relat Areas Mol Biol 73:135–182. doi:10.1002/9780470123195.ch5

    CAS  PubMed  Google Scholar 

  96. Zhang T, Berrocal JG, Frizzell KM et al (2009) Enzymes in the NAD+ salvage pathway regulate SIRT1 activity at target gene promoters. J Biol Chem 284(30):20408–20417. doi:10.1074/jbc.M109.016469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Rongvaux A, Shea RJ, Mulks MH, Gigot D, Urbain J, Leo O, Andris F (2002) Pre-B-cell colony-enhancing factor, whose expression is up-regulated in activated lymphocytes, is a nicotinamide phosphoribosyltransferase, a cytosolic enzyme involved in NAD biosynthesis. Eur J Immunol 32(11):3225–3234. doi:10.1002/1521-4141(200211)32:11,3225:AID-IMMU3225>3.0.CO;2-L

    Article  CAS  PubMed  Google Scholar 

  98. Raffaelli N, Sorci L, Amici A, Emanuelli M, Mazzola F, Magni G (2002) Identification of a novel human nicotinamide mononucleotide adenylyltransferase. Biochem Biophys Res Commun 297(4):835–840. doi:10.1016/S0006-291X(02)02285-4

    Article  CAS  PubMed  Google Scholar 

  99. Zhang Q, Piston DW, Goodman RH (2002) Regulation of corepressor function by nuclear NADH. Science 295(5561):1895–1897. doi:10.1126/science.1069300

    CAS  PubMed  Google Scholar 

  100. Dvir-Ginzberg M, Gagarina V, Lee EJ, Hall DJ (2008) Regulation of cartilage-specific gene expression in human chondrocytes by SirT1 and nicotinamide phosphoribosyltransferase. J Biol Chem 283(52):36300–36310. doi:10.1074/jbc.M803196200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Feige JN, Auwerx J (2008) Transcriptional targets of sirtuins in the coordination of mammalian physiology. Curr Opin Cell Biol 20(3):303–309. doi:10.1046/j.ceb.2008.03.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Srere PA (1987) Complexes of sequential metabolic enzymes. Annu Rev Biochem 56:89–124. doi:10.1146/annurev.bi.56.070187.000513

    Article  CAS  PubMed  Google Scholar 

  103. Grubisha O, Smith BC, Denu JM (2005) Small molecule regulation of Sir2 protein deacetylases. FEBS J 272(18):4607–4616. doi:10.1111/j.1742-4658.2005.04862.x

    Article  CAS  PubMed  Google Scholar 

  104. Rodgers JT, Lerin C, Gerhart-Hines Z, Puigserver P (2008) Metabolic adaptations through the PGC-1 alpha and SIRT1 pathways. FEBS Lett 582(1):46–53. doi:10.1016/j.febslet.2007.11.034

    Article  CAS  PubMed  Google Scholar 

  105. Shan T, Ren Y, Wang Y (2013) Sirtuin 1 affects the transcriptional expression of adipose triglyceride lipase in porcine adipocytes. J Anim Sci 91(3):1247–1254. doi:10.2527/jas.2011-5030

    Article  CAS  PubMed  Google Scholar 

  106. Revollo JR, Li X (2013) The ways and means that fine tune Sirt1 activity. Trends Biochem Sci 38(3):160–167. doi:10.1016/j.tibs.2012.12.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Massudi H, Grant R, Braidy N, Guest J, Farnsworth B, Guillemin GJ (2012) Age-associated changes in oxidative stress and NAD+ metabolism in human tissue. PLoS One 7(7):e42357. doi:10.1371/journal.pone.0042357

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Friebe D, Löffler D, Schönberg M, Bernhard F, Büttner P, Landgraf K, Kiess W, Körner A (2011) Impact of metabolic regulators on the expression of the obesity associated genes FTO and NAMPT in human preadipocytes and adipocytes. PLoS One 6(6):e19526. doi:10.1371/journal.pone.0019526

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Li D, Bi FF, Chen NN, Cao JM, Sun WP, Zhou YM, Li CY, Yang Q (2014) A novel crosstalk between BRCA1 and poly (ADP-ribose) polymerase 1 in breast cancer. Cell Cycle 13(21):3442–3449. doi:10.4161/15384101.2014.956507

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Sun LJ, Li SC, Zhao YH, Yu JW, Kang P, Yan BZ (2013) Silent information regulator 1 inhibition induces lipid metabolism disorders of hepatocytes and enhances hepatitis C virus replication. Hepatol Res 43(12):1343–1351. doi:10.1111/hepr.12089

    Article  CAS  PubMed  Google Scholar 

  111. Dietrich LS, Fuller L, Yero IL, Martinez L (1966) Nicotinamide mononucleotide pyrophosphorylase activity in animal tissues. J Biol Chem 241(1):188–191

    CAS  PubMed  Google Scholar 

  112. Belenky P, Bogan KL, Brenner C (2007) NAD(+) metabolism in health and disease. Trends Biochem Sci 32:12–19. doi:10.1016/j.tibs.2006.11.006

    Article  CAS  PubMed  Google Scholar 

  113. Cantó C, Houtkooper RH, Pirinen E et al (2012) The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab 15:838–847. doi:10.1016/j.cmet.2012.04.022

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  114. Duncan MT, DeLuca TA, Kuo HY, Yi M, Mrksich M, Miller WM (2016) SIRT1 is a critical regulator of K562 cell growth, survival, and differentiation. Exp Cell Res 344(1):40–52. doi:10.1016/j.yexcr.2016.04.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Mai A, Massa S, Lavu S et al (2005) Design, synthesis, and biological evaluation of sirtinol analogues as class III histone/protein deacetylase (Sirtuin) inhibitors. J Med Chem 48(24):7789–7795. doi:10.1021/jm050100l

    Article  CAS  PubMed  Google Scholar 

  116. Solomon JM, Pasupuleti R, Xu L, McDonagh T, Curtis R, DiStefano PS, Huber LJ (2006) Inhibition of SIRT1 catalytic activity increases p53 acetylation but does not alter cell survival following DNA damage. Mol Cell Biol 26(1):28–38. doi:10.1128/MCB.26.1.28-38.2006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Suzuki T, Imai K, Nakagawa H, Miyata N (2006) 2-Anilinobenzamides as SIRT inhibitors. ChemMedChem 1(10):1059–1062. doi:10.1002/cmdc.200600162

    Article  CAS  PubMed  Google Scholar 

  118. Taylor DM, Maxwell MM, Luthi-Carter R, Kazantsev AG (2008) Biological and potential therapeutic roles of sirtuin deacetylases. Cell Mol Life Sci 65(24):4000–4018. doi:10.1007/s00018-008-8357-y

    Article  CAS  PubMed  Google Scholar 

  119. Lin QQ, Yan CF, Lin R, Zhang JY, Wang WR, Yang LN, Zhang KF (2012) SIRT1 regulates TNF-alpha-induced expression of CD40 in 3T3-L1 adipocytes via NF-kappaB pathway. Cytokine 60(2):447–455. doi:10.1016/j.cyto.2012.05.025

    Article  CAS  PubMed  Google Scholar 

  120. Busch F, Mobasheri A, Shayan P, Stahlmann R, Shakibaei M (2012) Sirt-1 is required for the inhibition of apoptosis and inflammatory responses in human tenocytes. J Biol Chem 287(31):25770–25781. doi:10.1074/jbc.M112.355420

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Kunimoto R, Jimbow K, Tanimura A et al (2014) SIRT1 regulates lamellipodium extension and migration of melanoma cells. J Invest Dermatol 134(6):1693–1700. doi:10.1038/jid.2014.50

    Article  CAS  PubMed  Google Scholar 

  122. Kim YH, Bae JU, Lee SJ, Park SY, Kim CD (2015) SIRT1 attenuates PAF-induced MMP-2 production via down-regulation of PAF receptor expression in vascular smooth muscle cells. Vascul Pharmacol 72:35–42. doi:10.1016/j.vph.2015.04.015

    Article  CAS  PubMed  Google Scholar 

  123. Zheng T, Lu Y (2015) SIRT1 protects human lens epithelial cells against oxidative stress by inhibiting p53-dependent apoptosis. Curr Eye Res. doi:10.3109/02713683.2015.1093641

    Google Scholar 

  124. Lou Y, Wang Z, Xu Y, Zhou P, Cao J, Li Y, Chen Y, Sun J, Fu L (2015) Resveratrol prevents doxorubicin-induced cardiotoxicity in H9c2 cells through the inhibition of endoplasmic reticulum stress and the activation of the Sirt1 pathway. Int J Mol Med 36(3):873–880. doi:10.3892/ijmm.2015.2291

    CAS  PubMed  Google Scholar 

  125. Cambray-Deakin MA, Burgoyne RD (1987) Acetylated and detyrosinated alpha-tubulins are co-localized in stable microtubules in rat meningeal fibroblasts. Cell Motil Cytoskeleton 8(3):284–291. doi:10.1002/cm.970080309

    Article  CAS  PubMed  Google Scholar 

  126. North BJ, Marshall BL, Borra MT, Denu JM, Verdin E (2003) The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase. Mol Cell 11(2):437–444. doi:10.1016/S1097-2765(03)00038-8

    Article  CAS  PubMed  Google Scholar 

  127. Green KN, Steffan JS, Martinez-Coria H et al (2008) Nicotinamide restores cognition in Alzheimer’s disease transgenic mice via a mechanism involving sirtuin inhibition and selective reduction of Thr231-phosphotau. J Neurosci 28(45):11500–11510. doi:10.1523/JNEUROSCI.3203-08.2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Jiang S, Wang W, Miner J, Fromm M (2012) Cross regulation of sirtuin 1, AMPK, and PPARgamma in conjugated linoleic acid treated adipocytes. PLoS One 7(11):e48874. doi:10.1371/journal.pone.0048874

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Zhang Y, Sun J, Yu X, Shi L, Du W, Hu L, Liu C, Cao Y (2016) SIRT1 regulates accumulation of oxidized LDL in HUVEC via the autophagy-lysosomal pathway. Prostaglandins Other Lipid Mediat 122:37–44. doi:10.1016/j.prostaglandins.2015.12.005

    Article  CAS  PubMed  Google Scholar 

  130. Lee SJ, Choi SE, Jung IR, Lee KW, Kang Y (2013) Protective effect of nicotinamide on high glucose/palmitate-induced glucolipotoxicity to INS-1 beta cells is attributed to its inhibitory activity to sirtuins. Arch Biochem Biophys 535(2):187–196. doi:10.1016/j.abb.2013.03.011

    Article  CAS  PubMed  Google Scholar 

  131. Okawara M, Katsuki H, Kurimoto E, Shibata H, Kume T, Akaike A (2007) Resveratrol protects dopaminergic neurons in midbrain slice culture from multiple insults. Biochem Pharmacol 73(4):550–560. doi:10.1016/j.bcp.2006.11.003

    Article  CAS  PubMed  Google Scholar 

  132. Wu PF, Xie N, Zhang JJ et al (2013) Resveratrol preconditioning increases methionine sulfoxide reductases A expression and enhances resistance of human neuroblastoma cells to neurotoxins. J Nutr Biochem 24(6):1070–1077. doi:10.1016/j.jnutbio.2012.08.005

    Article  CAS  PubMed  Google Scholar 

  133. Wang W, Lin Q, Lin R, Zhang J, Ren F, Zhang J, Ji M, Li Y (2013) PPARalpha agonist fenofibrate attenuates TNF-alpha-induced CD40 expression in 3T3-L1 adipocytes via the SIRT1-dependent signaling pathway. Exp Cell Res 319(10):1523–1533. doi:10.1016/j.yexcr.2013.04.007

    Article  CAS  PubMed  Google Scholar 

  134. Wang XH, Zhu L, Hong X, Wang YT, Wang F, Bao JP, Xie XH, Lei L, Wu XT (2016) Resveratrol attenuated TNF-α–induced MMP-3 expression in human nucleus pulposus cells by activating autophagy via AMPK/SIRT1 signaling pathway. Exp Biol Med (Maywood) 241(8):848–853. doi:10.1177/1535370216637940

    Article  CAS  Google Scholar 

  135. Liu B, Zhang B, Guo R, Li S, Xu Y (2014) Enhancement in efferocytosis of oxidized low-density lipoprotein-induced apoptotic RAW264.7 cells through Sirt1-mediated autophagy. Int J Mol Med 33(3):523–533. doi:10.3892/ijmm.2013.1609

    CAS  PubMed  Google Scholar 

  136. Tarin JJ, Trounson AO, Sathananthan H (1999) Origin and ploidy of multipronuclear zygotes. Reprod Fertil Dev 11(4–5):273–279. doi:10.1071/RD99057

    Article  CAS  PubMed  Google Scholar 

  137. Senawong T, Peterson VJ, Avram D, Shepherd DM, Frye RA, Minucci S, Leid M (2003) Involvement of the histone deacetylase SIRT1 in chicken ovalbumin upstream promoter transcription factor (COUP-TF)-interacting protein 2-mediated transcriptional repression. J Biol Chem 278(44):43041–43050. doi:10.1074/jbc.M307477200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by a grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Korea (A121601).

Author information

Authors and Affiliations

  1. Department of Life Science, University of Seoul, Dongdaemungu, 163 Seoulsiripdaero, Seoul, 02504, Republic of Korea

    Eun Seong Hwang & Seon Beom Song

Authors
  1. Eun Seong Hwang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Seon Beom Song
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eun Seong Hwang.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hwang, E.S., Song, S.B. Nicotinamide is an inhibitor of SIRT1 in vitro, but can be a stimulator in cells. Cell. Mol. Life Sci. 74, 3347–3362 (2017). https://doi.org/10.1007/s00018-017-2527-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-017-2527-8

Keywords

Search

Navigation