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Nat Med. 2015 Aug;21(8):887-94. doi: 10.1038/nm.3882. Epub 2015 Jul 13.

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

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Division of Diabetes, Endocrinology and Metabolism, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomédica de Girona, Girona, and CIBERobn, Madrid, Spain.
Takeda Pharmaceuticals, Ltd., Osaka, Japan.
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.


Nicotinamide N-methyltransferase (Nnmt) methylates nicotinamide, a form of vitamin B3, to produce N(1)-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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