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

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  • Mizuno, Rin
    Inter-Organ Communication Research Team, Institute for Life and Medical Sciences, Kyoto University; Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine
  • Hojo, Hiroaki
    Inter-Organ Communication Research Team, Institute for Life and Medical Sciences, Kyoto University; The Thomas N. Sato BioMEC-X Laboratories, Advanced Telecommunications Research Institute International (ATR); ERATO Sato Live Bio-forecasting Project, Japan Science and Technology Agency (JST)
  • Takahashi, Masatomo
    Division of Metabolomics, Research Center for Transomics Medicine, Medical Institute of Bioregulation, Kyushu University
  • Kashio, Soshiro
    Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo
  • Enya, Sora
    The Thomas N. Sato BioMEC-X Laboratories, Advanced Telecommunications Research Institute International (ATR); ERATO Sato Live Bio-forecasting Project, Japan Science and Technology Agency (JST)
  • Nakao, Motonao
    Division of Metabolomics, Research Center for Transomics Medicine, Medical Institute of Bioregulation, Kyushu University
  • Konishi, Riyo
    Inter-Organ Communication Research Team, Institute for Life and Medical Sciences, Kyoto University
  • Yoda, Mayuko
    Inter-Organ Communication Research Team, Institute for Life and Medical Sciences, Kyoto University
  • Harata, Ayano
    Inter-Organ Communication Research Team, Institute for Life and Medical Sciences, Kyoto University
  • Hamanishi, Junzo
    Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine
  • Kawamoto, Hiroshi
    Laboratory of Immunology, Institute for Frontier Life and Medical Sciences, Kyoto University
  • Mandai, Masaki
    Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine
  • Suzuki, Yutaka
    Graduate School of Frontier Science, The University of Tokyo
  • Miura, Masayuki
    Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo
  • Bamba, Takeshi
    Division of Metabolomics, Research Center for Transomics Medicine, Medical Institute of Bioregulation, Kyushu University
  • Izumi, Yoshihiro
    Division of Metabolomics, Research Center for Transomics Medicine, Medical Institute of Bioregulation, Kyushu University
  • Kawaoka, Shinpei
    Inter-Organ Communication Research Team, Institute for Life and Medical Sciences, Kyoto University; The Thomas N. Sato BioMEC-X Laboratories, Advanced Telecommunications Research Institute International (ATR); ERATO Sato Live Bio-forecasting Project, Japan Science and Technology Agency (JST); Department of Integrative Bioanalytics, Institute of Development, Aging and Cancer (IDAC), Tohoku University

Description

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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