摘要
目的观察PPARγ靶向性激动剂罗格列酮对高脂、蛋氨酸-胆碱缺乏(MCD)饮食诱导的非酒精性脂肪性肝纤维化模型肝组织中转化生长因子(TGFβ1)及其下游效应因子结缔组织生长因子(CTGF)表达的影响,以明确其阻止脂肪性肝纤维化进展的作用及作用机制。方法采用MCD饮食8周建立C57BL6/J小鼠非酒精性脂肪性肝纤维化模型,以蛋氨酸-胆碱充足饮食设立对照组,干预组小鼠采用MCD饮食加罗格列酮(每日50mg/kg)喂养。血清丙氨酸氨基转移酶(ALT)采用全自动生化仪测定。HE染色、Masson染色观察肝脂肪变、炎症及纤维化程度。TGFβ1、CTGFmRNA及蛋白表达分别应用RT-PCR、免疫组织化学染色方法检测。结果模型组肝组织出现重度肝细胞脂肪变,伴有点、灶状肝细胞坏死及炎细胞浸润、汇管区纤维组织增生及窦周纤维化,ALT水平和TGFβ1、CTGFmRNA及蛋白表达均较对照组明显升高(P<0.05和P值均<0.01),罗格列酮干预组肝组织学改变较模型组明显减轻,ALT水平及TGFβ1、CTGF表达明显下降(P值均<0.05)。结论在MCD饮食诱导的小鼠非酒精性脂肪性肝纤维化模型中,罗格列酮可通过靶向激活PPARγ下调TGFβ1及其下游效应因子CTGF表达,从而缓解或阻止疾病的进展。
Objective To study the protective effect of peroxisome proliferator-activated receptor gamma （PPARγ） agonist, rosiglitazone, on advanced hepatic fibrosis induced by feeding mice with high fat, methionine-choline deficient （MCD） diet by determining the expression of transforming growth factor beta I （TGFβ1） and connective tissue growth factor （CTGF）. Methods An experimental model of non-alcoholic steatohepatitis/hepatie fibrosis was established by feeding male C57BL6/J mice with MCD diet for eight weeks. Control mice were fed methionine-choline supplemented diet the experiment group were given MCD diet plus rosiglitazone （50 mg · kg ^-1· d^-1 ） for 8 weeks. Serum alanine aminotransferase （ALT） was tested by enzymic method with automatic biochemistry analyzer. Hepatic steatosis, inflammation and fibrosis were graded and staged with HE and Masson staining. Expression of mRNA and protein of TGFβ1 and CTGF was analyzed by RT PCR and immunohistochemistry, respectively. Results Serum ALT and hepatic histopathology were normal in control mice. Severe steatosis with inflammatory infiltration, hepatic spot or focal necrosis, severe portal and sinus hepaticus fibrosis were developed in mice fed with MCD diet, and compared to control animals, serum ALT, mRNA and protein expression of TGFβ1 and CTGF were notably increased, （P〈0. 05 and both P〈0.01, respectively）. Rosiglitazone supplement prevented steatohepatitis/hepatic fibrosis progression, in consistent with the liver histology, both mRNA and protein expression of TGFβ1 and CTGF were significantly down regulated by rosiglitazone （both P〈0.05）. Conclusion MCD diet can induce hepatocytes damage and liver fibrosis, which might be inhibited by down regulation of expression of TGFβ1 and CTGF with PPARγ targeted agonist, rosiglitazone.
出处
《肝脏》
2008年第6期475-478,共4页
Chinese Hepatology
基金
王宝恩肝纤维化基金资助项目(20070021)
关键词
小鼠
肝纤维化
罗格列酮
转化生长因子Β1
结缔组织生长因子
Murine
Hepatic fibrosis
Rosiglitazone
Transforming growth factor beta 1
Connective tissue growth factor
