title: Deficiency of iNOS-derived NO accelerates lipid accumulation-independent liver fibrosis in non-alcoholic steatohepatitis mouse model.
abstract: BACKGROUND
  Although many of the factors and molecules closely associated with non-alcoholic steatohepatitis (NASH) have been reported, the role of inducible nitric oxide synthase (iNOS)-derived nitric oxide (NO) on the progression of NASH remains unclear. We therefore investigated the role of iNOS-derived NO in NASH pathogenesis with a long-term follow-up study using systemic iNOS-knockout mice under high-fat diet (HFD) conditions.
  
  
  METHODS
  iNOS-knockout and wild-type mice were fed a basal or HFD for 10 or 48 weeks. Lipid accumulation, fibrosis, and inflammation were evaluated, and various factors and molecules closely associated with NASH were analyzed.
  
  
  RESULTS
  Marked fibrosis and inflammation (indicators of NASH) were observed in the livers of iNOS-knockout mice compared to wild-type mice after 48 weeks of a HFD; however, lipid accumulation in iNOS-knockout mice livers was less than in the wild-type. Increased expressions of various cytokines that are transcriptionally controlled by NF-kB in iNOS-deficient mice livers were observed during HFD conditions.
  
  
  CONCLUSIONS
  iNOS-derived NO may play a protective role against the progression to NASH during an HFD by preventing fibrosis and inflammation, which are mediated by NF-kB activation in Kupffer cells. A lack of iNOS-derived NO accelerates progression to NASH without excessive lipid accumulation.
authors.affiliation: Division of Gastroenterology, Yokohama City University Graduate School of Medicine, 3-9 Fuku-ura, Kanazawa-ku, Yokohama, 236-0004, Japan. fwix0777@nifty.com.|Department of Gastroenterology, National Center for Global Health and Medicine, 1-21-1, Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan. fwix0777@nifty.com.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Nozaki
authors.affiliation: Division of Gastroenterology, Yokohama City University Graduate School of Medicine, 3-9 Fuku-ura, Kanazawa-ku, Yokohama, 236-0004, 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, Suita, Osaka, 565-0871, Japan. kwada@dent.osaka-u.ac.jp.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Wada
authors.affiliation: Division of Gastroenterology, Yokohama City University Graduate School of Medicine, 3-9 Fuku-ura, Kanazawa-ku, Yokohama, 236-0004, Japan. dryoneda@yahoo.co.jp.
authors.forename: Masato
authors.initials: M
authors.lastname: Yoneda
authors.affiliation: Division of Gastroenterology, Yokohama City University Graduate School of Medicine, 3-9 Fuku-ura, Kanazawa-ku, Yokohama, 236-0004, Japan. takaomi-kesso@hotmail.co.jp.
authors.forename: Takaomi
authors.initials: T
authors.lastname: Kessoku
authors.affiliation: Division of Gastroenterology, Yokohama City University Graduate School of Medicine, 3-9 Fuku-ura, Kanazawa-ku, Yokohama, 236-0004, Japan. shino@hyo-med.ac.jp.
authors.forename: Yoshiyasu
authors.initials: Y
authors.lastname: Shinohara
authors.affiliation: Division of Gastroenterology, Yokohama City University Graduate School of Medicine, 3-9 Fuku-ura, Kanazawa-ku, Yokohama, 236-0004, Japan. kento318@yokohama-cu.ac.jp.
authors.forename: Kento
authors.initials: K
authors.lastname: Imajo
authors.affiliation: Division of Gastroenterology, Yokohama City University Graduate School of Medicine, 3-9 Fuku-ura, Kanazawa-ku, Yokohama, 236-0004, Japan. yuji.ogawa01@gmail.com.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ogawa
authors.affiliation: Department of Gastroenterology, Kyushu Medical Center, National Hospital Organization, 1-8-1, Jigyohama, Chuo-ku, Fukuoka, 810-8563, Japan. nakamuta@kyumed.jp.
authors.forename: Makoto
authors.initials: M
authors.lastname: Nakamuta
authors.affiliation: Division of Gastroenterology, Yokohama City University Graduate School of Medicine, 3-9 Fuku-ura, Kanazawa-ku, Yokohama, 236-0004, 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, Ichikawa, 272-8516, 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, Yokohama, 236-0004, 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, Yokohama, 236-0004, Japan. terauchi-tky@umin.ac.jp.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Terauchi
authors.affiliation: Division of Gastroenterology, Yokohama City University Graduate School of Medicine, 3-9 Fuku-ura, Kanazawa-ku, Yokohama, 236-0004, Japan. nakajima-tky@umin.ac.jp.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nakajima
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002352:Carrier Proteins / Q000235:genetics; D024042:Collagen Type I / Q000235:genetics; D016207:Cytokines / Q000235:genetics; D051048:Diacylglycerol O-Acyltransferase / Q000235:genetics; D059305:Diet, High-Fat; D024202:Electrophoretic Mobility Shift Assay; D005230:Fatty Acids, Nonesterified / Q000032:analysis; D005500:Follow-Up Studies; D015870:Gene Expression; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008099:Liver / Q000737:chemistry* / Q000473:pathology; D008103:Liver Cirrhosis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000032:analysis / Q000172:deficiency / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics; D047493:PPAR alpha / Q000235:genetics; D010982:Platelet-Derived Growth Factor / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics; D013997:Time Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D014280:Triglycerides / Q000032:analysis
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002352:Carrier Proteins; D024042:Collagen Type I; D016207:Cytokines; D005230:Fatty Acids, Nonesterified; C506001:Mlxipl protein, mouse; D009687:Nuclear Proteins; D047493:PPAR alpha; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; C560825:Timp1 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1; D014157:Transcription Factors; D014280:Triglycerides; C106092:microsomal triglyceride transfer protein; D019716:Tissue Inhibitor of Metalloproteinase-2; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C516957:DGAT2 protein, mouse; D051048:Diacylglycerol O-Acyltransferase