Insufficiency of phosphatidylethanolamine N-methyltransferase is risk for lean non-alcoholic steatohepatitis

Atsuko Nakatsuka; Makoto Matsuyama; Satoshi Yamaguchi; Akihiro Katayama; Jun Eguchi; Kazutoshi Murakami; Sanae Teshigawara; Daisuke Ogawa; Nozomu Wada; Tetsuya Yasunaka; Fusao Ikeda; Akinobu Takaki; Eijiro Watanabe; Jun Wada

doi:10.1038/srep21721

Insufficiency of phosphatidylethanolamine N-methyltransferase is risk for lean non-alcoholic steatohepatitis

Atsuko Nakatsuka, Makoto Matsuyama, Satoshi Yamaguchi, Akihiro Katayama, Jun Eguchi, Kazutoshi Murakami, Sanae Teshigawara, Daisuke Ogawa, Nozomu Wada, Tetsuya Yasunaka, Fusao Ikeda, Akinobu Takaki, Eijiro Watanabe, Jun Wada

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Abstract

Although obesity is undoubtedly major risk for non-alcoholic steatohepatitis (NASH), the presence of lean NASH patients with normal body mass index has been recognized. Here, we report that the insufficiency of phosphatidylethanolamine N-methyltransferase (PEMT) is a risk for the lean NASH. The Pemt-/- mice fed high fat-high sucrose (HFHS) diet were protected from diet-induced obesity and diabetes, while they demonstrated prominent steatohepatitis and developed multiple liver tumors. Pemt exerted inhibitory effects on p53-driven transcription by forming the complex with clathrin heavy chain and p53, and Pemt-/- mice fed HFHS diet demonstrated prominent apoptosis of hepatocytes. Furthermore, hypermethylation and suppressed mRNA expression of F-box protein 31 and hepatocyte nuclear factor 4α resulted in the prominent activation of cyclin D1. PEMT mRNA expression in liver tissues of NASH patients was significantly lower than those with simple steatosis and we postulated the distinct clinical entity of lean NASH with insufficiency of PEMT activities.

Original language	English
Article number	21721
Journal	Scientific reports
Volume	6
DOIs	https://doi.org/10.1038/srep21721
Publication status	Published - Feb 17 2016

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@article{13ea47ac89424b7c854cde02c35b0859,

title = "Insufficiency of phosphatidylethanolamine N-methyltransferase is risk for lean non-alcoholic steatohepatitis",

abstract = "Although obesity is undoubtedly major risk for non-alcoholic steatohepatitis (NASH), the presence of lean NASH patients with normal body mass index has been recognized. Here, we report that the insufficiency of phosphatidylethanolamine N-methyltransferase (PEMT) is a risk for the lean NASH. The Pemt-/- mice fed high fat-high sucrose (HFHS) diet were protected from diet-induced obesity and diabetes, while they demonstrated prominent steatohepatitis and developed multiple liver tumors. Pemt exerted inhibitory effects on p53-driven transcription by forming the complex with clathrin heavy chain and p53, and Pemt-/- mice fed HFHS diet demonstrated prominent apoptosis of hepatocytes. Furthermore, hypermethylation and suppressed mRNA expression of F-box protein 31 and hepatocyte nuclear factor 4α resulted in the prominent activation of cyclin D1. PEMT mRNA expression in liver tissues of NASH patients was significantly lower than those with simple steatosis and we postulated the distinct clinical entity of lean NASH with insufficiency of PEMT activities.",

author = "Atsuko Nakatsuka and Makoto Matsuyama and Satoshi Yamaguchi and Akihiro Katayama and Jun Eguchi and Kazutoshi Murakami and Sanae Teshigawara and Daisuke Ogawa and Nozomu Wada and Tetsuya Yasunaka and Fusao Ikeda and Akinobu Takaki and Eijiro Watanabe and Jun Wada",

note = "Funding Information: Competing financial interests: Jun Wada receives speaker honoraria from Astellas, Boehringer Ingelheim, Novartis, Novo Nordisk, and Tanabe Mitsubishi, and receives grant support from Bayer, Daiichi Sankyo, Kyowa Hakko Kirin, MSD, Novo Nordisk, Otsuka, Torii, Pfizer, Takeda, Taisho Toyama and Tanabe Mitsubishi. Funding Information: This work was supported by JSPS Grant-in-Aid for Scientific Research, Grant numbers (25126716, 26293218, 26461361, and 26461362). AN is recipient of The Sanyo Broadcasting Foundation Award.",

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doi = "10.1038/srep21721",

language = "English",

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T1 - Insufficiency of phosphatidylethanolamine N-methyltransferase is risk for lean non-alcoholic steatohepatitis

AU - Nakatsuka, Atsuko

AU - Matsuyama, Makoto

AU - Yamaguchi, Satoshi

AU - Katayama, Akihiro

AU - Eguchi, Jun

AU - Murakami, Kazutoshi

AU - Teshigawara, Sanae

AU - Ogawa, Daisuke

AU - Wada, Nozomu

AU - Yasunaka, Tetsuya

AU - Ikeda, Fusao

AU - Takaki, Akinobu

AU - Watanabe, Eijiro

AU - Wada, Jun

N1 - Funding Information: Competing financial interests: Jun Wada receives speaker honoraria from Astellas, Boehringer Ingelheim, Novartis, Novo Nordisk, and Tanabe Mitsubishi, and receives grant support from Bayer, Daiichi Sankyo, Kyowa Hakko Kirin, MSD, Novo Nordisk, Otsuka, Torii, Pfizer, Takeda, Taisho Toyama and Tanabe Mitsubishi. Funding Information: This work was supported by JSPS Grant-in-Aid for Scientific Research, Grant numbers (25126716, 26293218, 26461361, and 26461362). AN is recipient of The Sanyo Broadcasting Foundation Award.

PY - 2016/2/17

Y1 - 2016/2/17

N2 - Although obesity is undoubtedly major risk for non-alcoholic steatohepatitis (NASH), the presence of lean NASH patients with normal body mass index has been recognized. Here, we report that the insufficiency of phosphatidylethanolamine N-methyltransferase (PEMT) is a risk for the lean NASH. The Pemt-/- mice fed high fat-high sucrose (HFHS) diet were protected from diet-induced obesity and diabetes, while they demonstrated prominent steatohepatitis and developed multiple liver tumors. Pemt exerted inhibitory effects on p53-driven transcription by forming the complex with clathrin heavy chain and p53, and Pemt-/- mice fed HFHS diet demonstrated prominent apoptosis of hepatocytes. Furthermore, hypermethylation and suppressed mRNA expression of F-box protein 31 and hepatocyte nuclear factor 4α resulted in the prominent activation of cyclin D1. PEMT mRNA expression in liver tissues of NASH patients was significantly lower than those with simple steatosis and we postulated the distinct clinical entity of lean NASH with insufficiency of PEMT activities.

AB - Although obesity is undoubtedly major risk for non-alcoholic steatohepatitis (NASH), the presence of lean NASH patients with normal body mass index has been recognized. Here, we report that the insufficiency of phosphatidylethanolamine N-methyltransferase (PEMT) is a risk for the lean NASH. The Pemt-/- mice fed high fat-high sucrose (HFHS) diet were protected from diet-induced obesity and diabetes, while they demonstrated prominent steatohepatitis and developed multiple liver tumors. Pemt exerted inhibitory effects on p53-driven transcription by forming the complex with clathrin heavy chain and p53, and Pemt-/- mice fed HFHS diet demonstrated prominent apoptosis of hepatocytes. Furthermore, hypermethylation and suppressed mRNA expression of F-box protein 31 and hepatocyte nuclear factor 4α resulted in the prominent activation of cyclin D1. PEMT mRNA expression in liver tissues of NASH patients was significantly lower than those with simple steatosis and we postulated the distinct clinical entity of lean NASH with insufficiency of PEMT activities.

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ER -

Insufficiency of phosphatidylethanolamine N-methyltransferase is risk for lean non-alcoholic steatohepatitis

Abstract

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