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

Takashi Moriya, Kazuya Kitamori, Hisao Naito, Yukie Yanagiba, Yuki Ito, Nozomi Yamagishi, Hazuki Tamada, Xiaofang Jia, Satoru Tsuchikura, Katsumi Ikeda, Yukio Yamori, Tamie Nakajima

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Abstract

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-α (TNF-α) and hepatic p50/p65 signals, but reduced hepatic Cu2+/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 α1 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 α1 type I collagen production and reduced triglyceride synthesis indicated extensive liver fibrosis at 16 weeks in this novel SHRSP5/Dmcr model.

Original languageEnglish
Pages (from-to)444-456
Number of pages13
JournalEnvironmental Health and Preventive Medicine
Volume17
Issue number6
DOIs
Publication statusPublished - 01-11-2012

All Science Journal Classification (ASJC) codes

  • Public Health, Environmental and Occupational Health

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    Moriya, T., Kitamori, K., Naito, H., Yanagiba, Y., Ito, Y., Yamagishi, N., Tamada, H., Jia, X., Tsuchikura, S., Ikeda, K., Yamori, Y., & Nakajima, T. (2012). Simultaneous changes in high-fat and high-cholesterol diet-induced steatohepatitis and severe fibrosis and those underlying molecular mechanisms in novel SHRSP5/Dmcr rat. Environmental Health and Preventive Medicine, 17(6), 444-456. https://doi.org/10.1007/s12199-012-0273-y