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Nicotinamide-N-methyltransferase is essential for SAM and 1-methylnicotinamide homeostasis in the AML12 hepatocyte cell line

Mayuko Yoda, Rin Mizuno, Yoshihiro Izumi, Masatomo Takahashi, Takeshi Bamba, Shinpei Kawaoka
doi: https://doi.org/10.1101/2022.09.25.509348
Mayuko Yoda
1Department of Integrative Bioanalytics, Institute of Development, Aging and Cancer (IDAC), Tohoku University, Sendai 980-8575, Japan
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Rin Mizuno
2Inter-Organ Communication Research Team, Institute for Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan
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Yoshihiro Izumi
3Division of Metabolomics, Research Center for Transomics Medicine, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan
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Masatomo Takahashi
3Division of Metabolomics, Research Center for Transomics Medicine, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan
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Takeshi Bamba
3Division of Metabolomics, Research Center for Transomics Medicine, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan
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Shinpei Kawaoka
1Department of Integrative Bioanalytics, Institute of Development, Aging and Cancer (IDAC), Tohoku University, Sendai 980-8575, Japan
2Inter-Organ Communication Research Team, Institute for Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan
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  • For correspondence: kawaokashinpei@gmail.com
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Abstract

Nicotinamide-N-methyltransferase (NNMT) is an enzyme that consumes S-adenosyl-methionine (SAM) and nicotinamide (NAM) to produce S-adenosyl-homocysteine (SAH) and 1-methylnicotinamide (MNAM). How much NNMT contributes to the quantity regulation of these four metabolites depends on whether NNMT is a major consumer or producer of these metabolites, which varies among various cellular contexts. Yet, whether NNMT critically regulates these metabolites in the AML12 hepatocyte cell line has been unexplored. To address this, we knock down Nnmt in AML12 cells and investigate the effects of Nnmt RNAi on metabolism and gene expression. We find that Nnmt RNAi accumulates SAM and SAH, whereas it reduces MNAM with NAM being unaltered. These results indicate that NNMT is a significant consumer of SAM and critical for MNAM production in this cell line. Moreover, transcriptome analyses reveal that altered SAM and MNAM homeostasis is accompanied by various detrimental molecular phenotypes, as exemplified by the down-regulations of lipogenic genes such as Srebf1. Consistent with this, oil-red O-staining experiments demonstrate the decrease of total lipids upon Nnmt RNAi. These results suggest that NNMT maintains proper SAM and MNAM homeostasis, providing an additional example where NNMT plays a critical role in regulating SAM and MNAM metabolism.

Competing Interest Statement

The authors have declared no competing interest.

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Posted September 27, 2022.
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Nicotinamide-N-methyltransferase is essential for SAM and 1-methylnicotinamide homeostasis in the AML12 hepatocyte cell line
Mayuko Yoda, Rin Mizuno, Yoshihiro Izumi, Masatomo Takahashi, Takeshi Bamba, Shinpei Kawaoka
bioRxiv 2022.09.25.509348; doi: https://doi.org/10.1101/2022.09.25.509348
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Nicotinamide-N-methyltransferase is essential for SAM and 1-methylnicotinamide homeostasis in the AML12 hepatocyte cell line
Mayuko Yoda, Rin Mizuno, Yoshihiro Izumi, Masatomo Takahashi, Takeshi Bamba, Shinpei Kawaoka
bioRxiv 2022.09.25.509348; doi: https://doi.org/10.1101/2022.09.25.509348

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