title: Deficiency of eNOS exacerbates early-stage NAFLD pathogenesis by changing the fat distribution.
abstract: BACKGROUND
  Although many factors and molecules that are closely associated with non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) have been reported, the role of endothelial nitric oxide synthase (eNOS)-derived nitric oxide (NO) in the pathogenesis of NAFLD/NASH remains unclear. We therefore investigated the role of eNOS-derived NO in NAFLD pathogenesis using systemic eNOS-knockout mice fed a high-fat diet.
  
  
  METHODS
  eNOS-knockout and wild-type mice were fed a basal diet or a high-fat diet for 12 weeks. Lipid accumulation and inflammation were evaluated in the liver, and various factors that are closely associated with NAFLD/NASH and hepatic tissue blood flow were analyzed.
  
  
  RESULTS
  Lipid accumulation and inflammation were more extensive in the liver and lipid accumulation was less extensive in the visceral fat tissue in eNOS-knockout mice, compared with wild-type mice, after 12 weeks of being fed a high-fat diet. While systemic insulin resistance was comparable between the eNOS-knockout and wild-type mice fed a high-fat diet, hepatic tissue blood flow was significantly suppressed in the eNOS-knockout mice, compared with the wild-type mice, in mice fed a high-fat diet. The microsomal triglyceride transfer protein activity was down-regulated in eNOS-knockout mice, compared with wild-type mice, in mice fed a high-fat diet.
  
  
  CONCLUSIONS
  A deficiency of eNOS-derived NO may exacerbate the early-stage of NASH pathogenesis by changing the fat distribution in a mouse model via the regulation of hepatic tissue blood flow.
authors.affiliation: Department of Gastroenterology, Yokohama City University Graduate School of Medicine, 3-9 Fuku-ura, Kanazawa-ku, 236-0004, Yokohama, Kanagawa, Japan. fwix0777@nifty.com.|Department of Gastroenterology, National Center for Global Health and Medicine, 1-21-1, Toyama, Shinjuku-ku, 162-8655, Tokyo, Japan. fwix0777@nifty.com.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Nozaki
authors.affiliation: Department of Gastroenterology, Yokohama City University Graduate School of Medicine, 3-9 Fuku-ura, Kanazawa-ku, 236-0004, Yokohama, Kanagawa, Japan. kfujita0819@gmail.com.
authors.forename: Koji
authors.initials: K
authors.lastname: Fujita
authors.affiliation: Department of Pharmacology, Graduate School of Dentistry, Osaka University, 1-8 Yamadaoka, 565-0871, Suita, Osaka, Japan. kwada@dent.osaka-u.ac.jp.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Wada
authors.affiliation: Department of Gastroenterology, Yokohama City University Graduate School of Medicine, 3-9 Fuku-ura, Kanazawa-ku, 236-0004, Yokohama, Kanagawa, Japan. dryoneda@yahoo.co.jp.
authors.forename: Masato
authors.initials: M
authors.lastname: Yoneda
authors.affiliation: Department of Gastroenterology, Yokohama City University Graduate School of Medicine, 3-9 Fuku-ura, Kanazawa-ku, 236-0004, Yokohama, Kanagawa, Japan. shino@hyo-med.ac.jp.
authors.forename: Yoshiyasu
authors.initials: Y
authors.lastname: Shinohara
authors.affiliation: Department of Gastroenterology, Yokohama City University Graduate School of Medicine, 3-9 Fuku-ura, Kanazawa-ku, 236-0004, Yokohama, Kanagawa, Japan. kento318@yokohama-cu.ac.jp.
authors.forename: Kento
authors.initials: K
authors.lastname: Imajo
authors.affiliation: Department of Gastroenterology, Yokohama City University Graduate School of Medicine, 3-9 Fuku-ura, Kanazawa-ku, 236-0004, Yokohama, Kanagawa, Japan. yuji.ogawa01@gmail.com.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ogawa
authors.affiliation: Department of Gastroenterology, Yokohama City University Graduate School of Medicine, 3-9 Fuku-ura, Kanazawa-ku, 236-0004, Yokohama, Kanagawa, Japan. takaomi-kesso@hotmail.co.jp.
authors.forename: Takaomi
authors.initials: T
authors.lastname: Kessoku
authors.affiliation: Department of Gastroenterology, Kyushu Medical Center, National Hospital Organization, 1-8-1, Jigyohama, Chuo-ku, 810-8563, Fukuoka, Japan. nakamuta@kyumed.jp.
authors.forename: Makoto
authors.initials: M
authors.lastname: Nakamuta
authors.affiliation: Department of Gastroenterology, Yokohama City University Graduate School of Medicine, 3-9 Fuku-ura, Kanazawa-ku, 236-0004, Yokohama, Kanagawa, Japan. ssai1423@yokohama-cu.ac.jp.
authors.forename: Satoru
authors.initials: S
authors.lastname: Saito
authors.affiliation: The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1, Konodai, 272-8516, Ichikawa, China, Japan. nmasaki@hospk.ncgm.go.jp.
authors.forename: Naohiko
authors.initials: N
authors.lastname: Masaki
authors.affiliation: Department of Molecular Pathology, Yokohama City University Graduate School of Medicine, 3-9 Fuku-ura, Kanazawa-ku, 236-0004, Yokohama, Kanagawa, Japan. ynagas@med.yokohama-cu.ac.jp.|Department of Surgical Pathology, Tokyo Women`s Medical University, 8-1, Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan. ynagas@med.yokohama-cu.ac.jp.
authors.forename: Yoji
authors.initials: Y
authors.lastname: Nagashima
authors.affiliation: Department of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine, 3-9 Fuku-ura, Kanazawa-ku, 236-0004, Yokohama, Kanagawa, Japan. terauchi-tky@umin.ac.jp.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Terauchi
authors.affiliation: Department of Gastroenterology, Yokohama City University Graduate School of Medicine, 3-9 Fuku-ura, Kanazawa-ku, 236-0004, Yokohama, Kanagawa, Japan. nakajima-tky@umin.ac.jp.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nakajima
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008099:Liver / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency* / Q000235:genetics; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism / Q000473:pathology*
chemical_list: D002352:Carrier Proteins; C106092:microsomal triglyceride transfer protein; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse