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 and Shinpei Kawaoka ()
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Rin Mizuno: Kyoto University
Hiroaki Hojo: Kyoto University
Masatomo Takahashi: Kyushu University
Soshiro Kashio: The University of Tokyo
Sora Enya: Advanced Telecommunications Research Institute International (ATR)
Motonao Nakao: Kyushu University
Riyo Konishi: Kyoto University
Mayuko Yoda: Kyoto University
Ayano Harata: Kyoto University
Junzo Hamanishi: Kyoto University Graduate School of Medicine
Hiroshi Kawamoto: Kyoto University
Masaki Mandai: Kyoto University Graduate School of Medicine
Yutaka Suzuki: The University of Tokyo
Masayuki Miura: The University of Tokyo
Takeshi Bamba: Kyushu University
Yoshihiro Izumi: Kyushu University
Shinpei Kawaoka: Kyoto University

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract 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.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30926-z

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DOI: 10.1038/s41467-022-30926-z

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