title: The modulation of hepatic adenosine triphosphate and inflammation by eicosapentaenoic acid during severe fibrotic progression in the SHRSP5/Dmcr rat model.
abstract: OBJECTIVE
  Eicosapentaenoic acid (EPA) can ameliorate certain liver lesions involved in non-alcoholic steatohepatitis (NASH). A previous study has found that stroke-prone spontaneously hypertensive 5/Dmcr (SHRSP5/Dmcr) rats fed a high fat-cholesterol (HFC) diet developed fibrotic steatohepatitis with histological similarities to NASH. This study evaluated the potential effects and mechanisms of action of EPA supplementation using this rodent model.
  
  
  METHODS
  Male rats were randomly assigned to groups that were fed with either the stroke-prone (SP) diet or HFC diet with or without EPA for 2, 8 and 14 weeks, respectively. The liver histopathology, biochemical features, mRNA and protein levels, and nuclear factor-κB (NF-κB) DNA binding activity were determined.
  
  
  RESULTS
  The SP diet-fed rats presented normal livers. Conversely, the HFC diet-fed rats developed microvesicular/macrovesicular steatosis, inflammation, ballooning degeneration and severe fibrosis. At 2 weeks, the administration of EPA inhibited hepatic inflammatory recruitment by blocking the phosphorylation of inhibitor of κB-α (IκBα), which antagonizes the NF-κB activation pathway. The dietary supplementation of EPA for 8 weeks ameliorated hepatic triglyceride accumulation and macrovesicular steatosis by inhibiting the HFC diet-induced decrease in the protein levels of enzymes involved in fatty acid β-oxidation including carnitine palmitoyltransferase 1, very long chain acyl-CoA dehydrogenase and peroxisomal bifunctional protein. Although the administration of EPA elicited no histologically detectable effects on severe fibrosis at 14 weeks, it restored an HFC diet-induced decline in hepatic adenosine triphosphate (ATP) levels and suppressed ballooning degeneration, suggesting that EPA may inhibit HFC diet-induced ATP loss and cell death.
  
  
  CONCLUSIONS
  Initial amelioration of the inflammation and steatosis in the rats after EPA supplementation indicates a possibility to treat steatohepatitis. Additionally, this study provides new insights into the roles of EPA in hepatic ATP depletion and subsequent hepatocellular injury during severe fibrosis.
authors.affiliation: Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Jia
authors.forename: Hisao
authors.initials: H
authors.lastname: Naito
authors.forename: Husna
authors.initials: H
authors.lastname: Yetti
authors.forename: Hazuki
authors.initials: H
authors.lastname: Tamada
authors.forename: Kazuya
authors.initials: K
authors.lastname: Kitamori
authors.forename: Yumi
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Nozomi
authors.initials: N
authors.lastname: Yamagishi
authors.forename: Dong
authors.initials: D
authors.lastname: Wang
authors.forename: Yukie
authors.initials: Y
authors.lastname: Yanagiba
authors.forename: Yuki
authors.initials: Y
authors.lastname: Ito
authors.forename: Juncai
authors.initials: J
authors.lastname: Wang
authors.forename: Naoki
authors.initials: N
authors.lastname: Tanaka
authors.forename: Katsumi
authors.initials: K
authors.lastname: Ikeda
authors.forename: Yukio
authors.initials: Y
authors.lastname: Yamori
authors.forename: Tamie
authors.initials: T
authors.lastname: Nakajima
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D004041:Dietary Fats / Q000008:administration & dosage; D019587:Dietary Supplements; D004195:Disease Models, Animal; D018450:Disease Progression; D015118:Eicosapentaenoic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy* / Q000503:physiopathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D011918:Rats, Inbred SHR; D012720:Severity of Illness Index; D013997:Time Factors
chemical_list: D004041:Dietary Fats; D016328:NF-kappa B; D012333:RNA, Messenger; D000255:Adenosine Triphosphate; D015118:Eicosapentaenoic Acid