【摘要】 目的观察PPARγ靶向性激动剂罗格列酮对营养性非酒精性脂肪性肝纤维化模型肝组织基质金属蛋白酶(MMP)、金属蛋白酶组织抑制因子(TIMP)表达的影响,探讨罗格列酮阻止脂肪性肝纤维化进展的作用机制。方法给予小鼠高脂、蛋氨酸-胆碱缺乏(MCD)饮食8周,建立非酒精性脂肪性肝纤维化模型,列入模型组(MCD-组,n=10);将蛋氨酸-胆碱充足饮食小鼠列入对照组(MCD+组,n=10);将接受MCD饮食加罗格列酮干预的小鼠列入干预组(MCD-+R组,n=10)。HE染色及Masson染色观察肝脂肪变、炎症活动及纤维化程度。RT-PCR和Westernblotting检测MMP-2、MMP-9、TIMP-1、TIMP-2的mRNA及蛋白表达。结果MCD+组动物肝组织学未见明显异常。MCD-组动物肝组织学呈现重度肝细胞脂肪变,伴有点状和灶状肝细胞坏死、炎性细胞浸润、汇管区纤维组织增生及窦周纤维化;MMP-2、MMP-9mRNA及蛋白表达与对照组相比均明显减弱(P<0.05),而TIMP-1、TIMP-2mRNA及蛋白表达则显著增强(P<0.05);MCD-+R组动物肝组织学改变与MCD-组比较均明显改善,MMP-2、MMP-9mRNA及蛋白表达较MCD-组明显上调(P<0.05);TIMP-1、TIMP-2mRNA及蛋白表达则明显降低(P<0.05)。结论在高脂、MCD饮食诱导的非酒精性脂肪性肝纤维化小鼠模型中,罗格列酮可通过激活PPARγ而上调MMPI、抑制TIMP的表达,从而延缓或阻止脂肪性肝纤维化进展。更多还原

【Abstract】 Objective To study the effects of rosiglitazone,a selective PPARγ agonist,on the expressions of matrix metalloproteinase(MMP) and tissue inhibitor of metalloproteinase(TIMP) in rats with nonalcoholic steato-hepatic fibrosis,and elucidate the mechanism of rosiglitazone on attenuating the steato-hepatic fibrosis progression.Methods C57BL6/J rats,fed with high fat and methionine-choline deficient(MCD) diet for eight weeks to induce hepatic fibrosis,constituted the model group(MCD-group,n=10).Rats fed with methionine-choline adequate diet were controls(MCD+ group,n=10).Rats fed with methionine-choline adequate diet and rosiglitazone constituted the treatment group(MCD-+R group,n=10).HE and Masson-trichrome stain were used for the observation of steatosis,inflammatory response and the severity of hepatic fibrosis in liver sections.The expressions of mRNA and protein of MMP-2,MMP-9,TIMP-1 and TIMP-2 were detected by RT-PCR and Western blotting.Results No significant pathological finding was observed in rats in MCD+ group,while severe hepatic steatosis,punctual and focal hepatic cellular necrosis,inflammatory cell infiltration,fibroplasia and perisinuous fibrosis were shown in rats of MCD-group.The expressions of mRNA and protein of MMP-2 and MMP-9 in MCD-group were decreased compared with those in MCD+ group(P<0.05),while TIMP-1 and TIMP-2 expressions were increased significantly(P<0.05).Compared with those in MCD-group,the hepatic pathological changes were ameliorated,the expressions of MMP-2 and MMP-9 were up-regulated,and TIMP-1 and TIMP-2 expressions were down-regulated in MCD-+R group(P<0.05).Conclusions Rosiglitazone plays an important role in ameliorating the nonalcoholic steato-hepatic fibrosis.Such effect of rosiglitazone may be realized by activating PPARγ to up-regulate MMP and suppress TIMP expression.更多还原