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Simultaneous changes in high-fat and high-cholesterol diet-induced steatohepatitis and severe fibrosis and those underlying molecular mechanisms in novel SHRSP5/Dmcr rat.

Authors: Moriya, T  Kitamori, K  Naito, H  Yanagiba, Y  Ito, Y  Yamagishi, N  Tamada, H  Jia, X  Tsuchikura, S  Ikeda, K  Yamori, Y  Nakajima, T 
Citation: Moriya T, etal., Environ Health Prev Med. 2012 Mar 11.
Pubmed: (View Article at PubMed) PMID:22407906
DOI: Full-text: DOI:10.1007/s12199-012-0273-y

OBJECTIVES: 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-alpha (TNF-alpha) 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-beta1 (TGF-beta1) 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 alpha-smooth muscle actin (alpha-SMA), corresponding to evident liver fibrosis, at 8 weeks and by alpha(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-alpha 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-beta1 prior to the appearance of any evident liver fibrosis could be an early signal for progressive liver fibrosis, elevated PDGF-B and alpha-SMA levels signified evident liver fibrosis at 8 weeks, and subsequent increased alpha(1) type I collagen production and reduced triglyceride synthesis indicated extensive liver fibrosis at 16 weeks in this novel SHRSP5/Dmcr model.

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CRRD Object Information
CRRD ID: 6482858
Created: 2012-05-08
Species: All species
Last Modified: 2012-05-08
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.