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.
authors.affiliation: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Kita-ku, Okayama 700-8558, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Nakatsuka
authors.affiliation: Shigei Medical Research Institute, Minami-ku, Okayama 701-0202, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Matsuyama
authors.affiliation: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Kita-ku, Okayama 700-8558, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamaguchi
authors.affiliation: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Kita-ku, Okayama 700-8558, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Katayama
authors.affiliation: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Kita-ku, Okayama 700-8558, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Eguchi
authors.affiliation: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Kita-ku, Okayama 700-8558, Japan.|Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Kita-ku, Okayama 700-8558, Japan.
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Murakami
authors.affiliation: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Kita-ku, Okayama 700-8558, Japan.
authors.forename: Sanae
authors.initials: S
authors.lastname: Teshigawara
authors.affiliation: Department of Diabetic Nephropathy, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Kita-ku, Okayama 700-8558, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ogawa
authors.affiliation: Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Kita-ku, Okayama 700-8558, Japan.
authors.forename: Nozomu
authors.initials: N
authors.lastname: Wada
authors.affiliation: Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Kita-ku, Okayama 700-8558, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Yasunaka
authors.affiliation: Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Kita-ku, Okayama 700-8558, Japan.
authors.forename: Fusao
authors.initials: F
authors.lastname: Ikeda
authors.affiliation: Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Kita-ku, Okayama 700-8558, Japan.
authors.forename: Akinobu
authors.initials: A
authors.lastname: Takaki
authors.affiliation: Dainippon Sumitomo Pharma, 2-6-8 Doshomachi, Chuo-Ku, Osaka 541-0045, Japan.
authors.forename: Eijiro
authors.initials: E
authors.lastname: Watanabe
authors.affiliation: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Kita-ku, Okayama 700-8558, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Wada
mesh_terms: D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D033922:Clathrin Heavy Chains / Q000378:metabolism; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D015536:Down-Regulation; D055785:Gene Knockdown Techniques; D020022:Genetic Predisposition to Disease; D022781:Hepatocytes / Q000166:cytology*; D006801:Humans; D051379:Mice; D065626:Non-alcoholic Fatty Liver Disease / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D009765:Obesity / Q000517:prevention & control; D050918:Phosphatidylethanolamine N-Methyltransferase / Q000235:genetics* / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53; D033922:Clathrin Heavy Chains; C494489:PEMT protein, human; C559160:PEMT protein, mouse; D050918:Phosphatidylethanolamine N-Methyltransferase