Fasting promotes the expression of SIRT1, an NAD+-dependent protein deacetylase, via activation of PPARα in mice

Abstract

Calorie restriction (CR) extends lifespans in a wide variety of species. CR induces an increase in the NAD+/NADH ratio in cells and results in activation of SIRT1, an NAD+-dependent protein deacetylase that is thought to be a metabolic master switch linked to the modulation of lifespans. CR also affects the expression of peroxisome proliferator-activated receptors (PPARs). The three subtypes, PPARα, PPARγ, and PPARβ/δ, are expressed in multiple organs. They regulate different physiological functions such as energy metabolism, insulin action and inflammation, and apparently act as important regulators of longevity and aging. SIRT1 has been reported to repress the PPARγ by docking with its co-factors and to promote fat mobilization. However, the correlation between SIRT1 and other PPARs is not fully understood. CR initially induces a fasting-like response. In this study, we investigated how SIRT1 and PPARα correlate in the fasting-induced anti-aging pathways. A 24-h fasting in mice increased mRNA and protein expression of both SIRT1 and PPARα in the livers, where the NAD+ levels increased with increasing nicotinamide phosphoribosyltransferase (NAMPT) activity in the NAD+ salvage pathway. Treatment of Hepa1-6 cells in a low glucose medium conditions with NAD+ or NADH showed that the mRNA expression of both SIRT1 and PPARα can be enhanced by addition of NAD+, and decreased by increasing NADH levels. The cell experiments using SIRT1 antagonists and a PPARα agonist suggested that PPARα is a key molecule located upstream from SIRT1, and has a role in regulating SIRT1 gene expression in fasting-induced anti-aging pathways.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  1. 1.

    Dali-Youcef N, Lagouge M, Froelich S et al (2007) Sirtuins: the ‘magnificent seven’, function, metabolism and longevity. Ann Med 39:335–345

    Article  CAS  PubMed  Google Scholar 

  2. 2.

    Leibiger IB, Berggren PO (2006) Sirt1: a metabolic master switch that modulates lifespan. Nat Med 12:34–36

    Article  CAS  PubMed  Google Scholar 

  3. 3.

    Lin SJ, Ford E, Haigis M et al (2004) Calorie restriction extends yeast life span by lowering the level of NADH. Genes Dev 18:12–16

    Article  CAS  PubMed  Google Scholar 

  4. 4.

    Lin SJ, Kaeberlein M, Andalis AA et al (2002) Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration. Nature 418:344–348

    Article  CAS  PubMed  Google Scholar 

  5. 5.

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

    Article  CAS  PubMed  Google Scholar 

  6. 6.

    Rodgers JT, Lerin C, Haas W et al (2005) Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature 434:113–118

    Article  CAS  PubMed  Google Scholar 

  7. 7.

    Picard F, Kurtev M, Chung N et al (2004) Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature 429:771–776

    Article  CAS  PubMed  Google Scholar 

  8. 8.

    Picard F, Auwerx J (2002) PPARγ and glucose homeostasis. Annu Rev Nutr 22:167–197

    Article  CAS  PubMed  Google Scholar 

  9. 9.

    Masternak MM, Bartke A (2007) PPARs in calorie restricted and genetically long-lived mice. PPAR Res 2007:1–7

    Article  Google Scholar 

  10. 10.

    Rongvaux A, Shea RJ, Mulks MH et al (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 Immnol 32:32225–33234

    Google Scholar 

  11. 11.

    Langley E, Pearson M, Faretta M et al (2002) Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence. EMBO J 21:2383–2396

    Article  CAS  PubMed  Google Scholar 

  12. 12.

    Luo J, Nikolaev AY, Imai S et al (2001) Negative control of p53 by Sir2α promotes cell survival under stress. Cell 107:137–148

    Article  CAS  PubMed  Google Scholar 

  13. 13.

    Vaziri H, Dessain SK, Ng Eaton E et al (2001) hSIR2 (SIRT1) functions as an NAD-dependent p53 deacetylase. Cell 107:149–159

    Article  CAS  PubMed  Google Scholar 

  14. 14.

    Bragt MCE, Popeijus HE (2008) Peroxisome proliferator-activated receptors and the metabolic syndrome. Physiol Behav 94:187–197

    Article  CAS  PubMed  Google Scholar 

  15. 15.

    Aoyama T, Peters JM, Iritani N et al (1998) Altered constitutive expression of fatty acid-metabolizing enzymes in mice lacking the peroxisome proliferator-activated receptorα. J Biol Chem 273:5678–5684

    Article  CAS  PubMed  Google Scholar 

  16. 16.

    Motojima K, Passilly P, Peters JM et al (1998) Expression of putative fatty acid transporter genes are regulated by peroxisome proliferator-activated receptor α and γ activators in a tissue- and inducer specific manner. J Biol Chem 273:16710–16714

    Article  CAS  PubMed  Google Scholar 

  17. 17.

    Kersten S, Seydoux J, Peters JM et al (1999) Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting. J Clin Invest 103:1489–1498

    Article  CAS  PubMed  Google Scholar 

  18. 18.

    Corton JC, Apte U, Anderson SP et al (2004) Mimetics of caloric restriction include agonists of lipid-activated nuclear receptors. J Biol Chem 279:46204–46212

    Article  CAS  PubMed  Google Scholar 

  19. 19.

    Maswood N, Young J, Tilmonet E et al (2004) Caloric restriction increases neurotrophic factor levels and attenuates neurochemical and behavioral deficits in a primate model of Parkinson’s disease. Proc Natl Acad Sci USA 101:18171–18176

    Article  CAS  PubMed  Google Scholar 

  20. 20.

    Patel NV, Gordon MN, Connor KE et al (2005) Caloric restriction attenuates Aβ-deposition in Alzheimer transgenic models. Neurobiol Aging 26:995–1000

    Article  CAS  PubMed  Google Scholar 

  21. 21.

    Wang J, Ho L, Qin W et al (2005) Caloric restriction attenuates β-amyloid neuropathology in a mouse model of Alzheimer’s disease. FASEB J 19:659–661

    Article  PubMed  Google Scholar 

  22. 22.

    Selkoe DJ (1996) Amyloid β-protein and the genetics of Alzheimer’s disease. J Biol Chem 271:18295–18298

    CAS  PubMed  Google Scholar 

  23. 23.

    Chen J, Zhou Y, Mueller-Steiner S et al (2005) SIRT1 protects against microglia-dependent amyloid-β toxicity through inhibiting NF-κB signaling. J Biol Chem 280:40364–40374

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported in part by fund from the Central Research Institute of Fukuoka University. Our thanks go to Mr. Steven Sabotta for reading the manuscript.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Shinji Soeda.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Hayashida, S., Arimoto, A., Kuramoto, Y. et al. Fasting promotes the expression of SIRT1, an NAD+-dependent protein deacetylase, via activation of PPARα in mice. Mol Cell Biochem 339, 285–292 (2010). https://doi.org/10.1007/s11010-010-0391-z

Download citation

Keywords

  • SIRT1
  • PPARα
  • Calorie restriction
  • NAD+/NADH