title: Simultaneous changes in high-fat and high-cholesterol diet-induced steatohepatitis and severe fibrosis and  those underlying molecular mechanisms in novel SHRSP5/Dmcr rat.
abstract: OBJECTIVE
  The aim of this study was to identify the molecular mechanisms underlying high-fat and high-cholesterol (HFC) diet-induced steatohepatitis and associated liver fibrosis progression in a novel stroke-prone, spontaneously hypertensive 5/Dmcr (SHRSP5/Dmcr) rat model.
  
  
  METHODS
  SHRSP5/Dmcr rats were given the control or HFC-diet for 2, 8, and 16 weeks. Plasma and hepatic gene expression of key molecules involved in fatty acid oxidation, inflammation, oxidative stress, and fibrosis were subsequently analyzed.
  
  
  RESULTS
  Rats fed the HFC-diet showed increased plasma tumor necrosis factor-α (TNF-α) and hepatic p50/p65 signals, but reduced hepatic Cu(2+)/Zn(2+)-superoxide dismutase across the treatment period and reduced plasma total adiponectin at 8 weeks. In HFC-diet-fed rats, transforming growth factor-β1 (TGF-β1) was elevated prior to the appearance of obvious liver fibrosis pathology at 2 weeks, followed by elevations in platelet-derived growth factor-B (PDGF-B) and α-smooth muscle actin (α-SMA), corresponding to evident liver fibrosis, at 8 weeks and by α(1) type I collagen production at 16 weeks. The HFC-diet increased hepatic total cholesterol accumulation, although hepatic triglyceride declined by 0.3-fold from 2 to 16 weeks due to reduced hepatic triglyceride synthesis, as suggested by the diacylglycerol acyltransferase 1 and 2 measurements.
  
  
  CONCLUSIONS
  TNF-α and p50/p65 molecular signals appeared to be major factors for HFC-diet-induced hepatic inflammation and oxidative stress facilitating liver disease progression. While the up-regulation of TGF-β1 prior to the appearance of any evident liver fibrosis could be an early signal for progressive liver fibrosis, elevated PDGF-B and α-SMA levels signified evident liver fibrosis at 8 weeks, and subsequent increased α(1) type I collagen production and reduced triglyceride synthesis indicated extensive liver fibrosis at 16 weeks in this novel SHRSP5/Dmcr model.
authors.affiliation: Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Tsurumai-cho, Showa-ku, Nagoya, Aichi, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Moriya
authors.forename: Kazuya
authors.initials: K
authors.lastname: Kitamori
authors.forename: Hisao
authors.initials: H
authors.lastname: Naito
authors.forename: Yukie
authors.initials: Y
authors.lastname: Yanagiba
authors.forename: Yuki
authors.initials: Y
authors.lastname: Ito
authors.forename: Nozomi
authors.initials: N
authors.lastname: Yamagishi
authors.forename: Hazuki
authors.initials: H
authors.lastname: Tamada
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Jia
authors.forename: Satoru
authors.initials: S
authors.lastname: Tsuchikura
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: D000818:Animals; D015415:Biomarkers / Q000097:blood; D015153:Blotting, Western; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary / Q000009:adverse effects*; D059305:Diet, High-Fat / Q000009:adverse effects*; D004041:Dietary Fats / Q000097:blood; D004195:Disease Models, Animal; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005234:Fatty Liver / Q000097:blood / Q000209:etiology* / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood; D008099:Liver / Q000473:pathology; D008103:Liver Cirrhosis / Q000097:blood / Q000209:etiology* / Q000473:pathology; D008297:Male; D047493:PPAR alpha / Q000097:blood; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D015415:Biomarkers; D002791:Cholesterol, Dietary; D004041:Dietary Fats; D036341:Intercellular Signaling Peptides and Proteins; D047493:PPAR alpha; D012333:RNA, Messenger; D002784:Cholesterol