【摘要】 目的观察替米沙坦对非酒精性脂肪性肝炎(NASH)大鼠肝纤维化的疗效和对基质金属蛋白酶-13(MMP-13)及其抑制因子-1(TIMP-1)的表达和胰岛素抵抗的影响。方法 30只雄性SD大鼠随机分为正常对照组、模型组和替米沙坦干预组。模型组和干预组给予高脂饲料喂养16周诱发脂肪性肝炎,其中干预组于高脂喂养12周后,给予替米沙坦[5mg/(kg·d)]灌胃治疗4周。16周末处死所有动物。检测血清丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)及空腹胰岛素(FINS)、空腹血糖(FPG),并计算胰岛素抵抗指数(HOMA-IR),RT-PCR和Western blot法检测肝组织TIMP-1、MMP-13 mRNA和蛋白的表达水平。病理切片观察组织学改变,免疫组织化学法检测α-平滑肌肌动蛋白(α-SMA)的表达情况。结果模型组血清ALT,AST,FPG,FINS及HOMA-IR较正常组均显著升高(均P<0.01)。与模型组相比,干预组血清ALT,FPG,FINS及HOMA-IR均明显下降,差异具有统计学意义(均P<0.01)。AST与干预组相比存在下降趋势,但差异无统计学意义(P>0.05)。与模型组相比,替米沙坦可显著改善肝脏炎症活动度及肝纤维化程度(均P<0.01)。干预组HOMA-IR较模型组明显降低[(3.59±0.29)vs(6.23±0.19),P<0.01]。干预组肝组织α-SMA的表达明显减少,肝组织MMP-13 mRNA和蛋白的表达均增加,TIMP-1 mRNA和蛋白的表达均降低(均P<0.01)。结论替米沙坦对NASH大鼠具有改善胰岛素抵抗和抗肝纤维化的作用。更多还原

【Abstract】 Objective To study the effects of telmisartan on matrix metalloproteinase-13(MMP-13) and tissue inhibitor of metallo- proteinase-1(TIMP-1) expressions and insulin resistance in rat model of nonalcoholic steatohepatitis(NASH).Methods Thirty male SD rats were randomized into normal control group,NASH model group and telmisartan intervention group.The rats were given standard food in normal control group,while high fat diet for 16 weeks in the other two groups to induce NASH.In telmisartan intervention group, telmisartan[5 mg/(kg·d)]was adminstrated intragastrically for 4 weeks since the 12th week.All animals were sacrificed at 16 weeks. Serum levels of alanine aminotransferase(ALT),aspartate transaminase(AST),fasting blood glucose(FBG) and fasting insulin(FINS) were detected.Insulin sensitivity was evaluated by homeostasis model assessment of insulin resistance(HOMA-IR).Western blot and RT-PCR were used to measure TIMP-1 and MMP-13 expressions in hepatic tissue.Histological observation and immunohistochemical staining ofα-smooth muscle actin(α-SMA) were also performed.Results Serum levels of ALT,AST,FPG,FINS and HOMA-IR were significantly higher in NASH group than in normal control group(P<0.01).Compared with NASH group,serum levels of ALT,FPG, FINS and HOMA-IR decreased significantly(P<0.01),and AST level also decreased,but with no significance(P>0.05).Telmisartan improved significantly hepatic inflammation and fibrosis(P<0.01),decreased HOMA-IR significantly(P<0.01),reduced expresseions ofα-SMA and TIMP-1,and increased expressions of MMP-13 in hepatic tissue(P<0.01).Conclusion Telmisartan can improve insulin resistance and prevent hepatic fibrosis in NASH rats.更多还原