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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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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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