Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Tsurumai-cho, Showa-ku, Nagoya, Aichi, Japan.
Environ Health Prev Med. 2012 Nov;17(6):444-56. doi: 10.1007/s12199-012-0273-y. Epub 2012 Mar 11.
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.
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.
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.
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 α(1) type I collagen production and reduced triglyceride synthesis indicated extensive liver fibrosis at 16 weeks in this novel SHRSP5/Dmcr model.
本研究旨在鉴定新型易卒中型自发性高血压 5/Dmcr（SHRSP5/Dmcr）大鼠模型中高脂肪和高胆固醇（HFC）饮食诱导的脂肪性肝炎及相关肝纤维化进展的分子机制。
SHRSP5/Dmcr 大鼠给予对照或 HFC 饮食 2、8 和 16 周。随后分析参与脂肪酸氧化、炎症、氧化应激和纤维化的关键分子在血浆和肝组织中的基因表达。
给予 HFC 饮食的大鼠在整个治疗期间显示肿瘤坏死因子-α（TNF-α）和肝 p50/p65 信号增加，但肝铜锌超氧化物歧化酶减少，且在 8 周时血浆总脂联素减少。在 HFC 饮食喂养的大鼠中，转化生长因子-β1（TGF-β1）在 2 周时出现明显的肝纤维化病理之前升高，随后在 8 周时血小板衍生生长因子-B（PDGF-B）和α-平滑肌肌动蛋白（α-SMA）升高，对应于明显的肝纤维化，并在 16 周时出现α1 型 I 胶原生成。HFC 饮食增加了肝总胆固醇的蓄积，尽管由于二酰基甘油酰基转移酶 1 和 2 的测量，肝甘油三酯的合成减少了 0.3 倍，因此在 2 至 16 周期间肝甘油三酯下降。
TNF-α和 p50/p65 分子信号似乎是 HFC 饮食诱导的肝炎症和氧化应激促进肝病进展的主要因素。虽然 TGF-β1 的上调早于任何明显肝纤维化的出现可能是进行性肝纤维化的早期信号，但在 8 周时 PDGF-B 和α-SMA 水平的升高表明明显的肝纤维化，随后α1 型 I 胶原生成增加和甘油三酯合成减少表明在这个新的 SHRSP5/Dmcr 模型中 16 周时广泛的肝纤维化。
