Inter-Organ Communication Research Team, Institute for Life and Medical Sciences, Kyoto University, Kyoto, 606-8507, Japan.
Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, Japan.
Nat Commun. 2022 Jun 15;13(1):3346. doi: 10.1038/s41467-022-30926-z.
Cancers disrupt host homeostasis in various manners but the identity of host factors underlying such disruption remains largely unknown. Here we show that nicotinamide-N-methyltransferase (NNMT) is a host factor that mediates metabolic dysfunction in the livers of cancer-bearing mice. Multiple solid cancers distantly increase expression of Nnmt and its product 1-methylnicotinamide (MNAM) in the liver. Multi-omics analyses reveal suppression of the urea cycle accompanied by accumulation of amino acids, and enhancement of uracil biogenesis in the livers of cancer-bearing mice. Importantly, genetic deletion of Nnmt leads to alleviation of these metabolic abnormalities, and buffers cancer-dependent weight loss and reduction of the voluntary wheel-running activity. Our data also demonstrate that MNAM is capable of affecting urea cycle metabolites in the liver. These results suggest that cancers up-regulate the hepatic NNMT pathway to rewire liver metabolism towards uracil biogenesis rather than nitrogen disposal via the urea cycle, thereby disrupting host homeostasis.
癌症以各种方式扰乱宿主内环境稳态，但宿主中潜在的这种破坏的关键因素在很大程度上仍是未知的。在这里，我们发现烟酰胺-N-甲基转移酶（NNMT）是一种宿主因子，可介导荷瘤小鼠肝脏中的代谢功能障碍。多种实体瘤在远处增加了 Nnmt 的表达及其产物 1-甲基烟酰胺（MNAM）在肝脏中的表达。多组学分析显示，尿素循环受到抑制，同时伴随着氨基酸的积累，以及尿嘧啶生物合成在荷瘤小鼠肝脏中的增强。重要的是，Nnmt 的基因缺失导致这些代谢异常得到缓解，并缓冲了癌症依赖的体重减轻和自愿轮跑活动减少。我们的数据还表明，MNAM 能够影响肝脏中的尿素循环代谢物。这些结果表明，癌症上调肝脏 NNMT 途径，将肝脏代谢重定向到尿嘧啶生物合成，而不是通过尿素循环进行氮排泄，从而破坏宿主内环境稳态。
