Nicotinamide N-methyltransferase regulates hepatic nutrient metabolism through Sirt1 protein stabilization.
Nicotinamide N-methyltransferase regulates hepatic nutrient metabolism through Sirt1 protein stabilization.
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DOI：
10.1038/nm.3882
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发表时间：
2015-08
期刊：
影响因子：
82.9
通讯作者：
Pissios P
中科院分区：
文献类型：
--
作者：
Hong S;Moreno-Navarrete JM;Wei X;Kikukawa Y;Tzameli I;Prasad D;Lee Y;Asara JM;Fernandez-Real JM;Maratos-Flier E;Pissios P
烟酰胺N-甲基转移酶（Nnmt）甲基化烟酰胺，维生素B3的一种形式，以产生N1-甲基烟酰胺（MNAM）。Nnmt是脂肪细胞中新兴的代谢调节剂，但其在肝脏（具有最强Nnmt表达的组织）中的作用尚不清楚。尽管其整体高表达，但我们发现Nnmt的肝脏表达是高度可变的，并与小鼠和人类的多种代谢参数相关。此外，我们发现，抑制肝脏Nnmt表达在体内改变葡萄糖和胆固醇代谢和Nnmt在肝脏中的代谢作用是由其产物MNAM介导的。用MNAM补充高脂肪饮食降低小鼠血清和肝脏胆固醇和肝脏甘油三酯水平。从机制上讲，增加Nnmt表达或MNAM水平稳定了沉默调节蛋白1蛋白，这是其代谢益处所需的效果。总之，我们描述了一种新的维生素B3的调节途径，可以为代谢性疾病的治疗提供新的机会。
Nicotinamide N-methyltransferase (Nnmt) methylates nicotinamide, a form of vitamin B3, to produce N1-methylnicotinamide (MNAM). Nnmt is an emerging metabolic regulator in adipocytes but its role in the liver, a 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 in 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, which is required for their metabolic benefits. In summary, we describe a novel regulatory pathway for vitamin B3 that could provide a new opportunity for metabolic disease therapy.