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Environmental Health and Preventive Medicine

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01.11.2012 | Regular Article

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

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

Erschienen in: Environmental Health and Preventive Medicine | Ausgabe 6/2012

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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⁺/Zn²⁺-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.

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Titel: Simultaneous changes in high-fat and high-cholesterol diet-induced steatohepatitis and severe fibrosis and those underlying molecular mechanisms in novel SHRSP5/Dmcr rat
verfasst von: Takashi Moriya
Kazuya Kitamori
Hisao Naito
Yukie Yanagiba
Yuki Ito
Nozomi Yamagishi
Hazuki Tamada
Xiaofang Jia
Satoru Tsuchikura
Katsumi Ikeda
Yukio Yamori
Tamie Nakajima
Publikationsdatum: 01.11.2012
Verlag: Springer Japan
Erschienen in: Environmental Health and Preventive Medicine / Ausgabe 6/2012
Print ISSN: 1342-078X
Elektronische ISSN: 1347-4715
DOI: https://doi.org/10.1007/s12199-012-0273-y

Springer Medizin

Abstract

Objectives

Methods

Results

Conclusions

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Acknowledgment to reviewers who served in 2012