降脂药普罗布考改善NASH大鼠肝脏脂肪变性的机制  

Effect of probucol in improving hepatic steatosis in rats with non- alcoholic steatohepatitis and the mechanism

作　　者：吴蓉[1] 吴小翎[1] 刘波[1] 张伟[1] 高静[2] 肖晓秋[3] 张霞[1] 

机构地区：[1]重庆医科大学附属第二医院消化内科,重庆400010 [2]重庆医科大学附属第二医院病理科,重庆400010 [3]重庆医科大学生命科学研究院,重庆400016

出　　处：《南方医科大学学报》2014年第5期731-735,共5页Journal of Southern Medical University

基　　金：重庆市科委自然科学基金(CSTC;2010BB5105)

摘　　要：目的探讨降脂药物普罗布考对非酒精性脂肪性肝炎大鼠肝脏病理、血清学指标的改善作用、对肝脏胆汁酸受体FXR及下游基因、蛋白SHP、SREBP-1C表达的影响。方法雄性SD大鼠40只,随机平均分4组:(1)正常对照组,予普通饲料;(2)高脂组,予高脂饲料;(3)普罗布考对照组,予普通饲料及普罗布考灌胃(500 mg/kg·d-1);(4)普罗布考干预组,予高脂饲料及普罗布考灌胃(500 mg/kg·d-1)。15周后处死,检测各组大鼠血清转氨酶、血脂、胆汁酸,同时取肝组织,切片行HE染色及病理评分;RTPCR及Western Blot的方法检测肝组织FXR、SHP及SREBP-1C基因及蛋白的表达水平。结果与高脂组比较,普罗布考干预组肝脏脂肪变性及炎症浸润程度明显减轻,血清ALT(126.40±52.56 vs 80.18±22.90 U/L,P<0.01)、AST(250.40±30.45 vs 179.45±41.14 U/L,P<0.01)及胆固醇(2.7±0.2 vs 2.4±0.3 mmol/L,P<0.01)、游离脂肪酸(0.734±.0.11 vs 0.557±0.19 mmol/L,P<0.05),胆汁酸(48.3±11.6 vs 24.9±17.7μmol/L,P<0.01)的水平显著降低;FXR、SHP mRNA及蛋白表达水平显著上升(P<0.05),SREBP-1C mRNA及蛋白表达则显著降低(P<0.05)。结论普罗布考改善NASH大鼠肝功及肝脏脂肪变性的作用与上调胆汁酸受体FXR的表达水平有关。Objective To determine the effects of probucol on serum parameters and liver histopathology in rats with non-alcoholic steatohepatitis （NASH） and explore the mechanisms. Methods Forty male Sprague-Dawley rats were randomly assigned into 4 equal groups, namely the normal control group （NC group） with a standard feeding, high-fat diet group （HD group） fed with a high-fat diet, probucol （500 mg/kg daily） control group （NP group） fed with standard diet, and probucol group fed with a high-fat diet （HP group）. After 15 weeks of feeding, the rats were euthanized for histopathological inspection of the liver with HE staining and detection of farnesoid X receptor （FXR）, SHP and SREBP-1C expressions using semi-quantitative RT-PCR and Western blotting. Results After the 15-week feeding, the rats in HP group had significantly lower levels of serum ALT, AST, cholesterol, bile acid, and free fatty acid than those in HD group （P〈0.01 or 0.05）. Compared with the normal control group, high-fat diet feeding resulted in significantly decreased mRNA and protein levels of FXR and SHP （P〈0.05） and significantly increased SREBP-1C level （P〈0.05）. These high-fat diet-induced gene expression changes were reversed by probucol intervention （P〈0.05）. Conclusion Probucol treatment has beneficial effects on serum parameters, hepatic steatosis, and lobular inflammation in high-fat diet-induced NASH possibly by up-regulating FXR expression.

关 键 词：非酒精性脂肪性肝炎 普罗布考 法尼醇X受体 固醇调节元件结合蛋白1C 

分 类 号：R575[医药卫生—消化系统]