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

Mizuno, Rin Hojo, Hiroaki Takahashi, Masatomo Kashio, Soshiro Enya, Sora Nakao, Motonao Konishi, Riyo Yoda, Mayuko Harata, Ayano Hamanishi, Junzo Kawamoto, Hiroshi Mandai, Masaki Suzuki, Yutaka Miura, Masayuki Bamba, Takeshi Izumi, Yoshihiro Kawaoka, Shinpei 京都大学 DOI:10.1038/s41467-022-30926-z

2022

概要

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.

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