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Nicotinamide N-methyltransferase regulates hepatic nutrient metabolism through Sirt1 protein stabilization

Nature Medicine volume 21, pages 887–894 (2015)Cite this article

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Abstract

Nicotinamide N-methyltransferase (Nnmt) methylates nicotinamide, a form of vitamin B3, to produce N1-methylnicotinamide (MNAM). Nnmt has emerged as a metabolic regulator in adipocytes, but its role in the liver, the tissue with the strongest Nnmt expression, is not known. In spite of its overall high expression, here we find that hepatic expression of Nnmt is highly variable and correlates with multiple metabolic parameters in mice and humans. Further, we find that suppression of hepatic Nnmt expression in vivo alters glucose and cholesterol metabolism and that the metabolic effects of Nnmt in the liver are mediated by its product MNAM. Supplementation of high-fat diet with MNAM decreases serum and liver cholesterol and liver triglycerides levels in mice. Mechanistically, increasing Nnmt expression or MNAM levels stabilizes sirtuin 1 protein, an effect that is required for their metabolic benefits. In summary, we describe here a novel regulatory pathway for vitamin B3 that could provide a new opportunity for metabolic disease therapy.

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Figure 1: Nnmt regulates gluconeogenesis and cholesterol metabolism.
Figure 2: Human liver NNMT expression correlates with serum cholesterol and liver inflammation.
Figure 3: Sirt1 is necessary and sufficient for the metabolic effects of Nnmt.
Figure 4: Nnmt regulates Sirt1 protein stability through its product MNAM.
Figure 5: MNAM improves cholesterol and lipid homeostasis in DIO mice.

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References

  1. Haigis, M.C. & Sinclair, D.A. Mammalian sirtuins: biological insights and disease relevance. Annu. Rev. Pathol. 5, 253–295 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Houtkooper, R.H., Cantó, C., Wanders, R.J. & Auwerx, J. The secret life of NAD+: an old metabolite controlling new metabolic signaling pathways. Endocr. Rev. 31, 194–223 (2010).

    Article  CAS  PubMed  Google Scholar 

  3. Bogan, K.L. & Brenner, C. Nicotinic acid, nicotinamide, and nicotinamide riboside: a molecular evaluation of NAD+ precursor vitamins in human nutrition. Annu. Rev. Nutr. 28, 115–130 (2008).

    Article  CAS  PubMed  Google Scholar 

  4. Rodgers, J.T. et al. Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1. Nature 434, 113–118 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Nemoto, S., Fergusson, M.M. & Finkel, T. Nutrient availability regulates SIRT1 through a forkhead-dependent pathway. Science 306, 2105–2108 (2004).

    Article  CAS  PubMed  Google Scholar 

  6. Nemoto, S., Fergusson, M.M. & Finkel, T. SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1α. J. Biol. Chem. 280, 16456–16460 (2005).

    Article  PubMed  Google Scholar 

  7. Liu, Y. et al. A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange. Nature 456, 269–273 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Rodgers, J.T. & Puigserver, P. Fasting-dependent glucose and lipid metabolic response through hepatic sirtuin 1. Proc. Natl. Acad. Sci. USA 104, 12861–12866 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Erion, D.M. et al. SirT1 knockdown in liver decreases basal hepatic glucose production and increases hepatic insulin responsiveness in diabetic rats. Proc. Natl. Acad. Sci. USA 106, 11288–11293 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Ponugoti, B. et al. SIRT1 deacetylates and inhibits SREBP-1C activity in regulation of hepatic lipid metabolism. J. Biol. Chem. 285, 33959–33970 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Walker, A.K. et al. Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP. Genes Dev. 24, 1403–1417 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Li, Y. et al. AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice. Cell Metab. 13, 376–388 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Xu, F. et al. Lack of SIRT1 (mammalian Sirtuin 1) activity leads to liver steatosis in the SIRT1+/− mice: a role of lipid mobilization and inflammation. Endocrinology 151, 2504–2514 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Purushotham, A. et al. Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation. Cell Metab. 9, 327–338 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Wang, R.-H. et al. Hepatic Sirt1 deficiency in mice impairs mTorc2/Akt signaling and results in hyperglycemia, oxidative damage, and insulin resistance. J. Clin. Invest. (2011).

  16. Bordone, L. et al. SIRT1 transgenic mice show phenotypes resembling calorie restriction. Aging Cell 6, 759–767 (2007).

    Article  CAS  PubMed  Google Scholar 

  17. Banks, A.S. et al. SirT1 gain of function increases energy efficiency and prevents diabetes in mice. Cell Metab. 8, 333–341 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Pfluger, P.T., Herranz, D., Velasco-Miguel, S., Serrano, M. & Tschöp, M.H. Sirt1 protects against high-fat diet–induced metabolic damage. Proc. Natl. Acad. Sci. USA 105, 9793–9798 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Yoshino, J., Mills, K.F., Yoon, M.J. & Imai, S. Nicotinamide mononucleotide, a key NAD(+) intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab. 14, 528–536 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Cantó, C. et al. The NAD+ precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab. 15, 838–847 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Qiang, L. et al. Proatherogenic abnormalities of lipid metabolism in SirT1 transgenic mice are mediated through Creb deacetylation. Cell Metab. 14, 758–767 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kim, J.-E., Chen, J. & Lou, Z. DBC1 is a negative regulator of SIRT1. Nature 451, 583–586 (2008).

    Article  CAS  PubMed  Google Scholar 

  23. Zhao, W. et al. Negative regulation of the deacetylase SIRT1 by DBC1. Nature 451, 587–590 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kim, E.-J., Kho, J.-H., Kang, M.-R. & Um, S.-J. Active regulator of SIRT1 cooperates with SIRT1 and facilitates suppression of p53 activity. Mol. Cell 28, 277–290 (2007).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  26. Chalkiadaki, A. & Guarente, L. Sirtuins mediate mammalian metabolic responses to nutrient availability. Nat. Rev. Endocrinol. 8, 287–296 (2012).

    Article  CAS  PubMed  Google Scholar 

  27. Kraus, D. et al. Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity. Nature 508, 258–262 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kang-Lee, Y.A. et al. Metabolic effects of nicotinamide administration in rats. J. Nutr. 113, 215–221 (1983).

    Article  CAS  PubMed  Google Scholar 

  29. Scheller, T., Orgacka, H., Szumlanski, C.L. & Weinshilboum, R.M. Mouse liver nicotinamide N-methyltransferase pharmacogenetics: biochemical properties and variation in activity among inbred strains. Pharmacogenetics 6, 43–53 (1996).

    Article  CAS  PubMed  Google Scholar 

  30. Yan, L., Otterness, D.M., Craddock, T.L. & Weinshilboum, R.M. Mouse liver nicotinamide N-methyltransferase: cDNA cloning, expression, and nucleotide sequence polymorphisms. Biochem. Pharmacol. 54, 1139–1149 (1997).

    Article  CAS  PubMed  Google Scholar 

  31. Felsted, R.L. & Chaykin, S. N1-Methylnicotinamide oxidation in a number of mammals. J. Biol. Chem. 242, 1274–1279 (1967).

    CAS  PubMed  Google Scholar 

  32. Ghazalpour, A. et al. Hybrid mouse diversity panel: a panel of inbred mouse strains suitable for analysis of complex genetic traits. Mamm. Genome 23, 680–692 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Ford, J., Ahmed, S., Allison, S., Jiang, M. & Milner, J. JNK2-dependent regulation of SIRT1 protein stability. Cell Cycle 7, 3091–3097 (2008).

    Article  CAS  PubMed  Google Scholar 

  34. Gao, Z. et al. Sirtuin 1 (SIRT1) protein degradation in response to persistent c-Jun N-terminal kinase 1 (JNK1) activation contributes to hepatic steatosis in obesity. J. Biol. Chem. 286, 22227–22234 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Dong, S. et al. The REGγ proteasome regulates hepatic lipid metabolism through inhibition of autophagy. Cell Metab. 18, 380–391 (2013).

    Article  CAS  PubMed  Google Scholar 

  36. Guex, N. & Peitsch, M.C. SWISS-MODEL and the Swiss-PdbViewer: an environment for comparative protein modeling. Electrophoresis 18, 2714–2723 (1997).

    Article  CAS  PubMed  Google Scholar 

  37. Trott, O. & Olson, A.J. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem. 31, 455–461 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Sanner, M.F. Python: a programming language for software integration and development. J. Mol. Graph. Model. 17, 55–61 (1999).

    Article  Google Scholar 

  39. Chlopicki, S. et al. 1-Methylnicotinamide (MNA), a primary metabolite of nicotinamide, exerts anti-thrombotic activity mediated by a cyclooxygenase-2/prostacyclin pathway. Br. J. Pharmacol. 152, 230–239 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Bryniarski, K., Biedron, R., Jakubowski, A., Chlopicki, S. & Marcinkiewicz, J. Anti-inflammatory effect of 1-methylnicotinamide in contact hypersensitivity to oxazolone in mice; involvement of prostacyclin. Eur. J. Pharmacol. 578, 332–338 (2008).

    Article  CAS  PubMed  Google Scholar 

  41. Bartusś, M. et al. 1-Methylnicotinamide (MNA) prevents endothelial dysfunction in hypertriglyceridemic and diabetic rats. Pharmacol. Rep. 60, 127–138 (2008).

    Google Scholar 

  42. Li, Y. et al. Hepatic overexpression of SIRT1 in mice attenuates endoplasmic reticulum stress and insulin resistance in the liver. FASEB J. 25, 1664–1679 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kannt, A. et al. Association of nicotinamide-N-methyltransferase mRNA expression in human adipose tissue and the plasma concentration of its product, 1-methylnicotinamide, with insulin resistance. Diabetologia 58, 799–808 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kennedy, A.R. et al. A high-fat, ketogenic diet induces a unique metabolic state in mice. Am. J. Physiol. Endocrinol Metab. 292, E1724–E1739 (2007).

    Article  CAS  PubMed  Google Scholar 

  45. Estep, P.W., Warner, J.B. & Bulyk, M.L. Short-term calorie restriction in male mice feminizes gene expression and alters key regulators of conserved aging regulatory pathways. PLoS ONE 4, e5242 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Schadt, E.E. et al. Genetics of gene expression surveyed in maize, mouse and man. Nature 422, 297–302 (2003).

    Article  CAS  PubMed  Google Scholar 

  47. Ulanovskaya, O.A., Zuhl, A.M. & Cravatt, B.F. NNMT promotes epigenetic remodeling in cancer by creating a metabolic methylation sink. Nat. Chem. Biol. 9, 300–306 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Mato, J.M., Martínez-Chantar, M.L. & Lu, S.C. Methionine metabolism and liver disease. Annu. Rev. Nutr. 28, 273–293 (2008).

    Article  CAS  PubMed  Google Scholar 

  49. Chalkiadaki, A. & Guarente, L. High-fat diet triggers inflammation-induced cleavage of SIRT1 in adipose tissue to promote metabolic dysfunction. Cell Metab. 16, 180–188 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Peng, L. et al. Ubiquitinated sirtuin 1 (SIRT1) function is modulated during DNA damage-induced cell death and survival. J. Biol. Chem. 290, 8904–8912 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Schmeisser, K. et al. Role of sirtuins in lifespan regulation is linked to methylation of nicotinamide. Nat. Chem. Biol. 9, 693–700 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Li, X. et al. SIRT1 deacetylates and positively regulates the nuclear receptor LXR. Mol. Cell 28, 91–106 (2007).

    Article  CAS  PubMed  Google Scholar 

  53. Kemper, J.K. et al. FXR acetylation is normally dynamically regulated by p300 and SIRT1 but constitutively elevated in metabolic disease states. Cell Metab. 10, 392–404 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Kleiner, D.E. et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 41, 1313–1321 (2005).

    Article  PubMed  Google Scholar 

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Acknowledgements

We would like to thank F.F. Liu, D. Adams, A.M. Real and M.J. Lee for technical assistance and J.S. Flier for advice. We thank B.M. Spiegelman and P. Puigserver (Dana-Farber Cancer Center, Boston, MA) for the donation of the Sirt1 and FoxO1 adenoviruses, D.E. Cohen (Brigham and Women's Hospital, Boston, MA) for lipoprotein analysis and R. Ortiz (University Hospital of Girona, Spain) for the pathology evaluation of the human liver biopsies. This work was supported by grants from Takeda, the US National Institute of Health DK028082 (E.M.F.), DK083694 (P.P.), Boston Area Diabetes Endocrinology Research Center (BADERC) grant DK057521 (P.P.), and by grants FIS-PI11/00214 and FIS-PI12/02631 to J.M.F.R. from the Instituto de Salud Carlos III and Fondo Europeo de Desarrollo Regional (FEDER), Spain.

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  1. Iphigenia Tzameli

    Present address: Present address: Cell Press, Cambridge, Massachusetts, USA.,

Authors and Affiliations

  1. Division of Diabetes, Endocrinology and Metabolism, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA

    Shangyu Hong, Xiaojing Wei, Iphigenia Tzameli, Deepthi Prasad, Eleftheria Maratos-Flier & Pavlos Pissios

  2. Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomédica de Girona, Girona, and CIBERobn, Madrid, Spain

    Jose M Moreno-Navarrete & Jose Manuel Fernandez-Real

  3. Takeda Pharmaceuticals, Ltd., Osaka, Japan

    Yusuke Kikukawa

  4. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    Yoonjin Lee

  5. Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA

    John M Asara

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Contributions

S.H., Y.K., I.T. and P.P. designed, performed and interpreted experiments. X.W., D.P., Y.L. and J.M.A. performed experiments. E.M.-F. interpreted experiments. J.M.M.-N. and J.M.F.-R. performed and interpreted the human experiments. S.H., I.T., P.P. and E.M.-F. corrected the manuscript. P.P. conceived and managed the project and wrote the manuscript.

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Correspondence to Pavlos Pissios.

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Hong, S., Moreno-Navarrete, J., Wei, X. et al. Nicotinamide N-methyltransferase regulates hepatic nutrient metabolism through Sirt1 protein stabilization. Nat Med 21, 887–894 (2015). https://doi.org/10.1038/nm.3882

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