罗格列酮对非酒精性脂肪性肝炎大鼠环氧合酶-2的调节  

The effect of rosiglitazone in modulating cyclooxygenases-2 in nonalcoholic steatohepatitis rats

作　　者：朱风尚[1] 赵家胜[2] 刘苏[3] 杨长青[1] 郜恒骏[1] 陈锡美[1] 

机构地区：[1]同济大学附属同济医院消化科,上海200065 [2]同济大学附属同济医院内分泌科 [3]上海长征医院闸北分院消化科

出　　处：《中华消化杂志》2010年第8期544-549,共6页Chinese Journal of Digestion

摘　　要：目的探讨罗格列酮在治疗非酒精性脂肪性肝炎（NASH）大鼠中对过氧化物酶体增殖物激活受体（PPART）、核因子（NF）-kB、环氧合酶（cox）-2的影响。方法将30只SD大鼠均分为正常组、模型组和罗格列酮治疗组，除对照组外，其余两组予高脂连续饲养12周复制非酒精性脂肪性肝炎（NASH）模型。从第12周开始治疗组每天给予罗格列酮4mg／kg灌胃8周。第20周末处死动物，收集血清和肝组织，检测肝功能、血脂、糖代谢、氧化还原指标。采用HE和Masson染色观察肝脏病理变化。ELISA法检测血清肿瘤坏死因子-a和前列腺素E2水平。免疫组化法观察肝组织PPARg、NFKB和COX-2表达，荧光定量PCR和Western印迹法检测肝COX-2基因和蛋白表达变化。结果与模型组相比，治疗组脂肪变性、炎性反应和纤维化改善明显（P值均〈0．05）。同时模型组空腹血糖、血清胰岛素、胰岛素抵抗指数（HOMAIRI）升高，血清和肝组织脂代谢紊乱，总胆固醇、三酰甘油、低密度脂蛋白胆固醇、游离脂肪酸（FFA）升高，高密度脂蛋白胆固醇下降。治疗组在罗格列酮治疗后上述指标均明显好转。与模型组相比，治疗组丙氨酸转氨酶和天冬氨酸转氨酶明显下降，血清和肝组织总抗氧化能力、超氧化物歧化酶、过氧化氢酶、谷胱甘肽过氧化物酶明显升高，丙二醛明显下降。免疫组化显示模型组肝PPARγ表达下降、NF-kB和COX-2表达升高。定量PCR和Western印迹法显示模型组肝COX-2表达（0．57±0．08和2．83±0．24）较正常组（0．38±0．03和1．00±0．03）升高（P值分别=0．000和0．004），治疗组COX-2基因和蛋白均明显下降（1．84±0．13和0．55±0．06，P值均〈0．01）。结论罗格列酮可减轻氧化应激和胰岛素抵抗，可用于治疗NASH。其机制可能是通过激活PPAR7后抑制NF-KB和COX-2表达实现。Objective To evaluate the impact of rosiglitazone （Ros） on liver expression of peroxisome proliferator-activated receptor γ（PPARγ）, nuclear factor （NF-kB） and cyclooxygenase-2 （COX-2） in treatment of nonalcoholic steatohepatitis （NASH） rats. Methods Thirty Sprague-Dawley rats were divided into normal group, model group and Ros treated group with 10 each. Except the normal group, the other two groups were given high fat diet for 12 weeks for NASH model. The rats in Ros treated group were gavaged 4 mg/kg of Ros daily at the 12th week for 8 weeks. All rats were sacrificed at the 20th week for blood sample and liver tissue. Biochemical parameters of liver function, lipid metabolism, glycometabolism and antioxidant enzyme activities were measured. The histological change of the liver were assessed with HE and Masson staining. The level of tumor necrosis factor （TNF） a and prostaglandin E2 （PGE2） was measured using ELISA. The expression of PPARy, NF-kB and COX 2 was detected with immunohistochemistry. The mRNA and protein expressions of COX-2 were tested by real-time PCR and Western blotting, respectively. Results In comparison with model group, Ros treated group showed significant improvement in hepatic steatosis, inflammation and fibrosis（all P value〈0.05）. In model group, the serum levels of fasting blood glucose, insulin and HOMA insulin resistance index （HOMA-IRI）, total cholesterol （TC）, total triglyeride （TG）, low density lipoprotein cholesterol （LDL-C） and free fatty acids were increased, but HDL C level was decreased. All above parameters markedly improved after Ros treatment. The levels of ALT and AST, total anti-oxidation competence, superoxide dismutase, catalase, glutathione peroxidase and malondialdehyde in Ros treated group were significantly ameliorated when compared with those in model group. Immunohistochemistry showed that the expression of NF-kB and COX-2 was significantly elevated, but PPARy was decreased in model group. Real time PCR and Western

关 键 词：非酒精性脂肪性肝炎 罗格列酮 过氧化物酶体增生物激活受体 环氧合酶 核因子-KB 

分 类 号：R686[医药卫生—骨科学]