title: Nicotinamide N-methyltransferase regulates hepatic nutrient metabolism through Sirt1 protein stabilization.
abstract: 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.
authors.affiliation: Division of Diabetes, Endocrinology and Metabolism, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Shangyu
authors.initials: S
authors.lastname: Hong
authors.affiliation: Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomédica de Girona, Girona, and CIBERobn, Madrid, Spain.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Moreno-Navarrete
authors.affiliation: Division of Diabetes, Endocrinology and Metabolism, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Wei
authors.affiliation: Takeda Pharmaceuticals, Ltd., Osaka, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kikukawa
authors.affiliation: Division of Diabetes, Endocrinology and Metabolism, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Iphigenia
authors.initials: I
authors.lastname: Tzameli
authors.affiliation: Division of Diabetes, Endocrinology and Metabolism, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Deepthi
authors.initials: D
authors.lastname: Prasad
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Yoonjin
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.affiliation: Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomédica de Girona, Girona, and CIBERobn, Madrid, Spain.
authors.forename: Jose Manuel
authors.initials: JM
authors.lastname: Fernandez-Real
authors.affiliation: Division of Diabetes, Endocrinology and Metabolism, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Maratos-Flier
authors.affiliation: Division of Diabetes, Endocrinology and Metabolism, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Pavlos
authors.initials: P
authors.lastname: Pissios
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D059305:Diet, High-Fat; D005260:Female; D005947:Glucose / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D050903:Nicotinamide N-Methyltransferase / Q000502:physiology*; D056564:Sirtuin 1 / Q000502:physiology*
chemical_list: D002784:Cholesterol; D050903:Nicotinamide N-Methyltransferase; C494407:Nnmt protein, mouse; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D005947:Glucose