Pro-oxidant-mediated hepatic fibrosis and effects of antioxidant intervention in murine dietary steatohepatitis
Pro-oxidant-mediated hepatic fibrosis and effects of antioxidant intervention in murine dietary steatohepatitis
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DOI：
10.3892/ijmm_00000220
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发表时间：
2009-08-01
影响因子：
5.4
通讯作者：
George, Jacob
中科院分区：
文献类型：
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作者：
Phung, Nghi;Pera, Natasha;George, Jacob
通过使用维生素 E 或 L-2-氧噻唑烷-4-羧酸酯 (OTC)（一种促进谷胱甘肽合成的半胱氨酸前体）进行抗氧化干预，评估了蛋氨酸和胆碱缺乏 (MCD) 饮食诱导的脂肪性肝炎模型中氧化应激对纤维形成的机制意义。从第 3 周开始，喂食 MCD 饮食的小鼠中，肝脏还原型谷胱甘肽 (GSH) 显着减少，硫代巴比妥酸反应物质 (TBARS) 升高，这与肝损伤有关。从第 5 周起，肝星状细胞 (HSC) 激活、胶原蛋白 α(1)(I) mRNA 表达增加，以及形态纤维化就很明显。维生素 E 补充 GSH，减少 TBARS、脂肪变性、炎症、HSC 激活和胶原蛋白 α(1)(I) mRNA 表达，并改善纤维化。维生素E不影响促纤维化细胞因子（转化生长因子-β1、结缔组织生长因子）或基质重塑酶（金属蛋白酶-1和-2、基质金属蛋白酶-2和-13的组织抑制剂）的表达。尽管在补充 OTC 的小鼠中补充了肝脏 GSH，但在第 5 周时减少肝脏 TBARS 和抑制胶原蛋白 α(1)(I) mRNA 表达的最初益处未能保护这些小鼠在以后的时间点免受肝损伤或纤维化。在脂肪性肝炎的 MCD 模型中，氧化应激或脂质过氧化产物直接介导 HSC 活化和胶原蛋白基因表达。补充维生素E（而非谷胱甘肽）可以中断这一致病过程。
The mechanistic significance of oxidative stress to fibrogenesis in the methionine and choline-deficient (MCD) diet-induced model of steatohepatitis was evaluated by antioxidant intervention, using either vitamin E or L-2-oxothiazolidine-4-carboxylate (OTC), a cysteine precursor that promotes glutathione synthesis. Significant depletion of hepatic reduced glutathione (GSH) and elevation of thiobarbituric acid reactive substances (TBARS) occurred from week 3 in association with hepatic injury in mice fed the MCD diet. Hepatic stellate cell (HSC) activation and increased collagen alpha(1)(I) mRNA expression, together with morphologic fibrosis were evident from week 5. Vitamin E repleted GSH, reduced TBARS, steatosis, inflammation, HSC activation and collagen alpha(1)(I) mRNA expression, and ameliorated fibrosis. Vitamin E did not effect the expression of either profibrogenic cytokines (transforming growth factor-beta 1, connective tissue growth factor) or matrix remodeling enzymes (tissue inhibitor of metalloproteinase-1 and -2, matrix metalloproteinase-2 and -13). Despite repletion of hepatic GSH in OTC-supplemented mice, the initial benefit in the reduction of hepatic TBARS and inhibition of collagen alpha(1)(I) mRNA expression at week 5, failed to protect these mice from hepatic injury or fibrosis at later time points. Oxidative stress or products of lipid peroxidation mediate HSC activation and collagen gene expression directly in the MCD model of steatohepatitis. Vitamin E but not glutathione augmentation can interrupt this pathogenic process.