George Jacob, Pera Natasha, Phung Nghi, Leclercq Isabelle, Yun Hou Jing, Farrell Geoffrey
Storr Liver Unit, Westmead Millennium Institute, University of Sydney, Westmead Hospital, New South Wales, Sydney, Australia.
J Hepatol. 2003 Nov;39(5):756-64. doi: 10.1016/s0168-8278(03)00376-3.
BACKGROUND/AIMS: We explored the involvement of cell types, cytokines and lipid peroxidation in a rat dietary model of fibrosing steatohepatitis.
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.
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.
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.
背景/目的：我们在大鼠肝纤维化脂肪性肝炎饮食模型中探究了细胞类型、细胞因子及脂质过氧化的作用。
给雄性大鼠喂食缺乏蛋氨酸和胆碱的高脂饮食（MCD），持续17周。分析全肝、肝细胞及非实质细胞中的还原型谷胱甘肽（GSH）水平、脂质过氧化产物（硫代巴比妥酸反应性物质，TBARS）、肝损伤及纤维化情况。
喂食MCD饮食的大鼠在第2周出现肝脂肪变性，第5周出现局灶性坏死性炎症改变，而细胞周围纤维化在第12周至17周逐渐形成并进展。Ⅰ型胶原α1基因表达在第5周上调，至第17周增加了5倍。星状细胞是胶原基因表达的唯一来源。TIMP-1和TIMP-2在第12周增加。喂食MCD饮食的大鼠肝脏中GSH水平降低，TBARS升高。肝细胞是脂质过氧化的来源，且仅在该细胞类型中TGFβ1的mRNA水平升高。
“纤维化脂肪性肝炎”的MCD模型复制了人类脂肪性肝炎的组织学特征以及脂肪变性、炎性细胞损伤和纤维化形成的过程。其时间顺序与氧化损伤参与肝脏纤维化炎症募集和发病机制的概念一致。
