Remote solid cancers rewire hepatic nitrogen metabolism via host nicotinamide-N-methyltransferase

Rin Mizuno, Hiroaki Hojo, Masatomo Takahashi, Soshiro Kashio, Sora Enya, Motonao Nakao, Riyo Konishi, Mayuko Yoda, Ayano Harata, Junzo Hamanishi, Hiroshi Kawamoto, Masaki Mandai, Yutaka Suzuki, Masayuki Miura, Takeshi Bamba, Yoshihiro Izumi, Shinpei Kawaoka

研究成果: ジャーナルへの寄稿学術誌査読

抄録

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.

本文言語英語
論文番号3346
ジャーナルNature communications
13
1
DOI
出版ステータス出版済み - 12月 2022

!!!All Science Journal Classification (ASJC) codes

  • 化学 (全般)
  • 生化学、遺伝学、分子生物学(全般)
  • 一般
  • 物理学および天文学(全般)

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