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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 |
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| Authors: | Takashi Moriya Kazuya Kitamori Hisao Naito Yukie Yanagiba Yuki Ito Nozomi Yamagishi Hazuki Tamada Xiaofang Jia Satoru Tsuchikura Katsumi Ikeda Yukio Yamori Tamie Nakajima |
| Affiliation: | 1. Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan 2. Department of Food and Nutritional Environment, Kinjo Gakuin University, Nagoya, Aichi, Japan 3. Mechanism of Health Effects Research Group, National Institute of Occupational Safety and Health, Kawasaki, Kanagawa, Japan 4. Department of Occupational and Environmental Health, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan 5. Division of Breeding Management, Disease Model Cooperative Research Association, Kyoto, Japan 6. School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women??s University, Nishinomiya, Hyogo, Japan 7. Institute for World Health Development, Mukogawa Women??s University, Nishinomiya, Hyogo, Japan |
| Abstract: | ObjectivesThe 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.MethodsSHRSP5/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.ResultsRats 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.ConclusionsTNF-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.Electronic supplementary materialThe online version of this article (doi:10.1007/s12199-012-0273-y) contains supplementary material, which is available to authorized users. |
| Keywords: | Steatohepatitis Inflammation TNF-α NF-κb Fibrosis |
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