陈晶+李丽+叶月芳

[摘要] 目的 探讨青蒿琥酯对非酒精性脂肪性肝炎（NASH）大鼠肝组织过氧化物酶体增殖物激活受体γ（PPARγ）和固醇调节元件结合蛋白-1c（SREBP-1c）表达的影响。 方法 采用高脂饲料喂养的方法复制大鼠NASH模型，实验分正常组、模型组、易善复组、青蒿琥酯低剂量组、中剂量组和高剂量组。正常组每天予以标准饲料喂养，正常组和模型组给予同等剂量的生理盐水。给药治疗8周后，提取肝组织，运用免疫组化方法测定各组大鼠肝组织PPARγ、SREBP-1c 蛋白表达情况；采用硫代巴比妥酸法测定丙二醛（MDA）含量；采用黄嘌呤氧化酶法测定超氧化物歧化酶（SOD）含量；采用分光光度法测定谷胱甘肽-过氧化物酶（GSH-Px）含量；光镜观察肝脂肪变、炎症及纤维化程度。 结果 与正常组相比，在模型组中不仅PPARγ蛋白表达（1.67±1.01）明显减少，而且SREBP-1c蛋白表达（3.27±1.03）明显增多（均P < 0.01）；青蒿琥酯低中剂量组与模型组相比，PPARγ蛋白表达增多，SREBP-1c蛋白表达明显减少，并且呈剂量依赖性（均P < 0.05），青蒿琥酯高剂量组PPARγ为（3.21±1.02），SREBP-1c为（1.32±0.77），与模型组相比，差异均有高度统计学意义（P < 0.01）。与模型组相比，青蒿琥酯各剂量组能提高SOD和GSH-Px的含量，降低MDA的含量，并且呈剂量依赖性（均P < 0.05）；青蒿琥酯能明显改善大鼠肝组织脂肪变、炎症程度和肝纤维化程度。 结论 青蒿琥酯治疗大鼠NASH的机制可能与上调PPARγ和下调SREBP-1c的表达有关。

[关键词] 青蒿琥酯；非酒精性脂肪性肝炎；过氧化物酶体增殖物激活受体γ；固醇调节元件结合蛋白-1c

[中图分类号] R575.1 [文献标识码] A [文章编号] 1673-7210（2014）08（b）-0004-04

Effects of artesunate on expressions of peroxisome proliferators activated receptor γ and sterol regulatory element binding protein-1c in the hepatic tissue of the rats with nonalcoholic steatohepatitis

CHEN Jing LI Li YE Yuefang

Department of Gastroenterology， the Affiliated Hospital of Hangzhou Normal University， Zhejiang Province， Hangzhou 310015， China

[Abstract] Objective To explore the influence of artesunate upon expressions of peroxisome proliferator-activated receptor γ （PPARγ） and sterol regulatory element binding protein-1c （SREBP-1c） in the hepatic tissue of the rats with nonalcoholic steatohepatitis （NASH）. Methods High-fat diets were used in male SD rats to induce NASH. Rats were divided into six groups： normal group， model group， Essentiale Forte N group， artesunate low-dose group， moderate-dose group and high-dose group. Standard feed was used to the normal group every day. Equal volume of normal saline was applied to the normal group and the model group. After artesunate treatment for 8 weeks， the hepatic tissues of the rats were extracted， and the expressions of PPARγ and SREBP-1c in them were detected by immunohistochemistry assay. The contents of malondialdehyde （MDA） was measured with thiobarbituric acid assay， the contents of superoxide dismutase （SOD） was measured by xanthine oxidase assay， and the contents of GSH-Px was measured by spectrophotometry. The presence of hepatic fatty degeneration and the degree of inflammation and fibrosis were observed with light microscope. Results Not noly the expression of PPARγ decreased （1.67±1.01） significantly but also the expression of SREBP-1c increased（3.27±1.03） significantly in the model group compared with those of the normal group （all P < 0.05）. The expression of PPARγ increased and the expression of SREBP-1c decreased in a dose-dependent manner in the artesunate low and moderate-dose groups compared with those of the model group. The expression of PPARγ was （3.21±1.02） and the expression of SREBP-1c was （1.32±0.77） in the artesunate high-dose group， which had significant differences compared to those of the model group （all P < 0.01）. In the artesunate groups， both the contents of SOD and GSH-Px increased and the content of MDA decreased in a dose-dependent manner compared to those of the model group. Both the fatty degeneration and the degree of inflammation and hepatic fibrosis in rats were improved markedly by artesunate. Conclusion The mechanism of artesunate curing rat NASH may be associated with the up-regulation of PPARγ expression and the down-regulation of SREBP-1c expression.

[Key words] Artesunate； Nonalcoholic steatohepatitis； Peroxisome proliferator-activated receptors γ； Sterol regulatory element binding protein-1c

非酒精性脂肪性肝病（nonalcoholic fatty liver disease，NAFLD）是世界范围内常见肝脏疾病之一，近年来在我国的发病率迅速上升，是继病毒性肝炎后第2位常见肝病。NAFLD从病理上分为单纯性脂肪肝、脂肪性肝炎（NASH）、脂肪性肝纤维化和脂肪性肝硬化[1]。因此，NAFLD是对人类健康产生严重威胁的慢性肝病之一，对NAFLD发病机制及防治方法的探讨已经成为当前研究的核心，但其病理分子机制还不完全明确，故临床治疗上无特效药物且疗效欠佳。根据Day[2]提出的“二次打击学说”，本实验拟从其发病机制出发，研究过氧化物酶体增殖物激活受体γ（PPARγ）和固醇调节元件结合蛋白-1c（SREBP-1c）在脂肪代谢中的调节作用，初步探讨青蒿琥酯对NASH的保护作用。……