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

Research output: Contribution to journalArticle

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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 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 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

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High Fat Diet
Fatty Liver
Liver Cirrhosis
Fibrosis
Cholesterol
Liver
Proto-Oncogene Proteins c-sis
Triglycerides
Transforming Growth Factors
Collagen Type I
Oxidative Stress
Tumor Necrosis Factor-alpha
Diacylglycerol O-Acyltransferase
Inflammation
Adiponectin
Smooth Muscle
Disease Progression
Liver Diseases
Actins
Up-Regulation

All Science Journal Classification (ASJC) codes

  • Public Health, Environmental and Occupational Health

Cite this

Moriya, Takashi ; Kitamori, Kazuya ; Naito, Hisao ; Yanagiba, Yukie ; Ito, Yuki ; Yamagishi, Nozomi ; Tamada, Hazuki ; Jia, Xiaofang ; Tsuchikura, Satoru ; Ikeda, Katsumi ; Yamori, Yukio ; Nakajima, Tamie. / Simultaneous changes in high-fat and high-cholesterol diet-induced steatohepatitis and severe fibrosis and those underlying molecular mechanisms in novel SHRSP5/Dmcr rat. In: Environmental Health and Preventive Medicine. 2012 ; Vol. 17, No. 6. pp. 444-456.
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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 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 α1 type I collagen production and reduced triglyceride synthesis indicated extensive liver fibrosis at 16 weeks in this novel SHRSP5/Dmcr model.",
author = "Takashi Moriya and Kazuya Kitamori and Hisao Naito and Yukie Yanagiba and Yuki Ito and Nozomi Yamagishi and Hazuki Tamada and Xiaofang Jia and Satoru Tsuchikura and Katsumi Ikeda and Yukio Yamori and Tamie Nakajima",
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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. / Moriya, Takashi; Kitamori, Kazuya; Naito, Hisao; Yanagiba, Yukie; Ito, Yuki; Yamagishi, Nozomi; Tamada, Hazuki; Jia, Xiaofang; Tsuchikura, Satoru; Ikeda, Katsumi; Yamori, Yukio; Nakajima, Tamie.

In: Environmental Health and Preventive Medicine, Vol. 17, No. 6, 01.11.2012, p. 444-456.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Simultaneous changes in high-fat and high-cholesterol diet-induced steatohepatitis and severe fibrosis and those underlying molecular mechanisms in novel SHRSP5/Dmcr rat

AU - Moriya, Takashi

AU - Kitamori, Kazuya

AU - Naito, Hisao

AU - Yanagiba, Yukie

AU - Ito, Yuki

AU - Yamagishi, Nozomi

AU - Tamada, Hazuki

AU - Jia, Xiaofang

AU - Tsuchikura, Satoru

AU - Ikeda, Katsumi

AU - Yamori, Yukio

AU - Nakajima, Tamie

PY - 2012/11/1

Y1 - 2012/11/1

N2 - 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 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 α1 type I collagen production and reduced triglyceride synthesis indicated extensive liver fibrosis at 16 weeks in this novel SHRSP5/Dmcr model.

AB - 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 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 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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U2 - 10.1007/s12199-012-0273-y

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