论文部分内容阅读
目的 观察3-(5’-羟甲基-2’-呋喃基)-1苯甲基引唑(YC-1)靶向抑制缺氧诱导因子-1α对实验性大鼠非酒精性脂肪肝进程的影响. 方法 72只雄性SD大鼠随机分为正常组、模型组、干预组,通过高脂饲料喂养建立大鼠脂肪肝模型.造模后干预组每2周给予腹腔内注射YC-1(剂量为2 mg/kg),观察时间点分别为4周、8周、12周、16周.干预结束后取血及肝组织,进行血脂、肝功能生物化学指标、空腹血糖、胰岛素检测,病理组织学检查,计算胰岛素抵抗指数.用Realtime-PCR法检测肝组织中缺氧诱导因子-1α、过氧化物酶体增殖物激活受体α及核因子-κB的mRNA转录水平,Western blot检测蛋白质表达水平.多组计量资料比较采用成组设计的方差分析、Kruskal-Wallis H检验,两两比较采用LSD法,P＜0.05为差异有统计学意义. 结果 与模型组相比,干预组在连续给药12周后,大鼠血清ALT、AST、甘油三酯和总胆固醇水平明显下降(P＜0.05);与模型组比较,干预组在连续YC-1注射8周后,大鼠肝脏脂肪变明显减轻(P＜0.05),炎症程度也明显好转(P＜0.05),在连续YC-1注射12周后大鼠肝脏纤维化程度较模型组也显著下降(P＜0.05);在连续给药12周及16周后,过氧化物酶体增殖物激活受体α的mRNA表达较模型组显著上升,而核因子-κB的mRNA表达则显著下降.缺氧诱导因子-1α、过氧化物酶体增殖物激活受体α、核因子-κ B在各组不同时期脂肪肝组织中的蛋白质表达,与mRNA表达结果类似.与模型组相比,干预组各时间点的胰岛素抵抗指数差异无统计学意义.结论 靶向抑制缺氧诱导因子-1α能明显延缓实验性脂肪肝大鼠的进程,并改善脂质代谢,但对胰岛素抵抗无明显影响.“,”Objective To investigate the effect of targeted inhibition of hypoxia-inducible factor-lα (HIF-1 α) by 3-(5’-hydroxymethyl-2’-furyl)-l-benzylindazole (YC-1) on the progression of non-alcoholic fat liver diseases (NAFLD) in rats.Methods A total of 72 male Sprague-Dawley rats were randomly divided into normal group,model group,and intervention group,and the rats were given high-fat feed to establish the rat model of fatty liver disease.After the establishment of the model,the rats in the intervention group were given intraperitoneally injected YC-1 (at a dose of 2 mg/kg) every two weeks and were observed at 4,8,12,and 16 weeks.Blood samples and liver tissues were collected after the end of intervention,and blood lipid,biochemical markers for liver function,fasting blood glucose,and insulin were measured.Histopathological examinations were performed,and insulin resistance index was calculated.Real-time PCR was used to measure the mRNA transcriptional levels of HIF-1 αt,peroxisome proliferator-activated receptor α,and nuclear factorkappa B (NF-κB),and Western blot was used to measure their protein expression levels.An analysis of variance with group design and the Kruskal-Wallis H test were used for comparison of continuous data between multiple groups,and the least significant difference method was used for comparison between any two groups.P ＜0.05 was considered statistically significant.Results Compared with the model group,the intervention group had significant reductions in the senum levels of alanine aminotransferase,aspartate aminotransferase,triglyceride,and total cholesterol after 12 weeks of continuous administration (P ＜ 0.05);after 8 weeks of continuous injection of YC-1,the intervention group had significant alleviation in hepatic steatosis and significant improvement in infammation degree (P ＜ 0.05),and after 12 weeks of continuous injection of YC-1,the intervention group had a significant reduction in liver fibrosis degree (P ＜ 0.05);after 12 and 16 weeks of continuous administration,the intervention group had a significant increase in the mRNA expression of peroxisome proliferator-activated receptor αt and a significant reduction in the mRNA expression of NF-κB.The protein expression of HIF-1α,peroxisome proliferator-activated receptor α,and NF-κB in fatty liver tissues at different time points showed similar results as the mRNA expression.There were no significant differences in insulin resistance index at each time point between the model group and the intervention group.Conclusion Targeted inhibition of YC-1 can effectively delay the progression of experimental fatty liver disease and improve lipid metabolism,but it has no significant effect on insulin resistance.