NNMT activation can contribute to the development of fatty liver disease by modulating the NAD + metabolism

Motoaki Komatsu, Takeshi Kanda, Hidenori Urai, Arata Kurokochi, Rina Kitahama, Shuhei Shigaki, Takashi Ono, Hideo Yukioka, Kazuhiro Hasegawa, Hirobumi Tokuyama, Hiroshi Kawabe, Shu Wakino, Hiroshi Itoh

研究成果: Article査読

36 被引用数 (Scopus)

抄録

Nicotinamide N-methyltransferase (NNMT) catalyses the reaction between nicotinamide (NAM) and S-adenosylmethionine to produce 1-methylnicotinamide and S-adenosylhomocysteine. Recently, this enzyme has also been reported to modulate hepatic nutrient metabolism, but its role in the liver has not been fully elucidated. We developed transgenic mice overexpressing NNMT to elucidate its role in hepatic nutrient metabolism. When fed a high fat diet containing NAM, a precursor for nicotinamide adenine dinucleotide (NAD)+, these NNMT-overexpressing mice exhibit fatty liver deterioration following increased expression of the genes mediating fatty acid uptake and decreased very low-density lipoprotein secretion. NNMT overactivation decreased the NAD+ content in the liver and also decreased gene activity related to fatty acid oxidation by inhibiting NAD+-dependent deacetylase Sirt3 function. Moreover, the transgenic mice showed liver fibrosis, with the induction of inflammatory and fibrosis genes. Induced NNMT expression decreased the tissue methylation capacity, thereby reducing methylation of the connective tissue growth factor (CTGF) gene promoter, resulting in increased CTGF expression. These data indicate that NNMT links the NAD+ and methionine metabolic pathways and promotes liver steatosis and fibrosis. Therefore, targeting NNMT may serve as a therapeutic strategy for treating fatty liver and fibrosis.

本文言語English
論文番号8637
ジャーナルScientific reports
8
1
DOI
出版ステータスPublished - 2018 12月 1

ASJC Scopus subject areas

  • 一般

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