Lipid peroxidation, stellate cell activation and hepatic fibrogenesis in a rat model of chronic steatohepatitis
Lipid peroxidation, stellate cell activation and hepatic fibrogenesis in a rat model of chronic steatohepatitis
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DOI：
10.1016/s0168-8278(03)00376-3
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发表时间：
2003-11-01
影响因子：
25.7
通讯作者：
Farrell, G
中科院分区：
文献类型：
--
作者：
George, J;Pera, N;Farrell, G
背景/目的：我们探讨了细胞类型、细胞因子和脂质过氧化在纤维化性脂肪性肝炎大鼠饮食模型中的作用。方法：雄性大鼠饲喂缺乏蛋氨酸和胆碱（MCD）的高脂肪饲料长达17周。分析全肝、肝细胞和非实质细胞的谷胱甘肽（GSH）水平降低、脂质过氧化产物（硫代巴比妥酸反应性物质，TBARS）、肝损伤和纤维化。结果：MCD饮食喂养的大鼠在第2周发生肝脂肪变性，第5周发生局灶性坏死炎症改变，而细胞周围纤维化在第12周至第17周发生并进展。胶原α(1)(1)基因表达在第5周上调，在第17周增加了5倍。星状细胞是胶原蛋白基因表达的独特来源。TIMP-1和-2在第12周升高。MCD饮食喂养的大鼠肝脏表现出GSH水平降低和TBARS水平升高。肝细胞是脂质过氧化的来源，TGFbeta1的mRNA水平仅在这种细胞类型中升高。结论：“纤维化性脂肪性肝炎”MCD模型复制了人类脂肪性肝炎的组织学特征，并复制了脂肪变性、炎症细胞损伤和纤维化发生的顺序。时间顺序与氧化损伤参与炎症募集和肝纤维化发病机制的概念是一致的。(C) 2003年欧洲肝脏研究协会。Elsevier B.V.版权所有。
Background/Aims: We explored the involvement of cell types, cytokines and lipid peroxidation in a rat dietary model of fibrosing steatohepatitis.Methods: Male rats were fed a high fat diet deficient in methionine and choline (MCD) for up to 17 weeks. Whole liver, hepatocytes and non-parenchymal cells were analysed for reduced glutathione (GSH) levels, products of lipid peroxidation (thiobarbituric acid reactive substances, TBARS), liver injury, and fibrosis.Results: MCD diet-fed rats developed hepatic steatosis at week 2 and focal necroinflammatory change by week 5, while pericellular fibrosis evolved and progressed between weeks 12 and 17. Collagen alpha(1)(1) gene expression was upregulated by week 5 and increased fivefold by week 17. Stellate cells were the unique source of collagen gene expression. TIMP-1 and -2 were increased at week 12. Livers of MCD diet-fed rats exhibited lowered levels of GSH and elevated TBARS. Hepatocytes were the source of lipid peroxidation, and mRNA levels for TGFbeta1 were increased only in this cell type.Conclusions: The MCD model of 'fibrosing steatohepatitis' replicates the histologic features of human steatohepatitis, and the sequence of steatosis, inflammatory cell injury and fibrogenesis. The temporal sequence is consistent with a concept for involvement of oxidative injury in inflammatory recruitment and pathogenesis of hepatic fibrogenesis. (C) 2003 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.