黄芪总苷通过调控SIRT1表达对胆汁淤积性肝纤维化小鼠的影响  

Effects of astragalosides on mice with cholestatic hepatic fibrosis via SIRT1 expression

作　　者：周群 高思琦 张霖璋 张华[1] 刘伟[1] 刘平[1,2] 陈佳美 ZHOU Qun;GAO Si-qi;ZHANG Lin-zhang;ZHANG Hua;LIU Wei;LIU Ping;CHEN Jia-mei(Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine,Institute of Liver Diseases,Shanghai University of Traditional Chinese Medicine,Ministry of Education Key Laboratory of Liver and Kidney Diseases,Shanghai Key Laboratory of Traditional Chinese Medicine for Clinical Medicine,Shanghai 201203,China;Institute of Interdisciplinary Integrative Medicine Research,Shanghai University of Traditional Chinese Medicine,Shanghai Frontiers Science Center of TCM Chemical Biology,Shanghai 201203,China)

机构地区：[1]上海中医药大学附属曙光医院,上海市中医药研究院肝病研究所,肝肾疾病病证教育部重点实验室,上海市中医临床重点实验室,上海201203 [2]上海中医药大学交叉科学研究院,上海市中医药化学生物学前沿基地,上海201203

出　　处：《中成药》2023年第11期3568-3576,共9页Chinese Traditional Patent Medicine

基　　金：国家自然科学基金重点项目(82130120);国家自然科学基金面上项目(81973613);上海市青年科技启明星计划基金项目(19QA1408900)。

摘　　要：目的探究黄芪总苷对胆汁淤积性肝纤维化小鼠的影响及其作用机制。方法采用2种胆汁淤积性肝纤维化模型,0.1%DDC喂养C57BL/6小鼠8周,第5周起灌胃给予黄芪总苷112、56 mg/kg和奥贝胆酸4周;Mdr2^(-/-)小鼠8周龄时灌胃给予黄芪总苷56、28 mg/kg和奥贝胆酸3周,对照组和模型组分别灌胃给予等体积蒸馏水。给药结束后检测各组小鼠肝质量与肝脏系数、血清肝功能、肝组织病理学变化和肝组织纤维化相关指标的表达。结果与对照组比较,DDC和Mdr2^(-/-)模型组小鼠肝质量和肝脏系数均升高(P<0.01),血清ALT、AST、ALP活性和TBA、胆红素水平均升高(P<0.01),肝组织病理可见结构紊乱、大量炎性细胞浸润,汇管区胶原沉积,胶原阳性面积和肝组织HYP水平均增加(P<0.01),肝组织α-SMA、Col1a1、Col4a1和TGF-β1表达均升高(P<0.01),SIRT1表达降低(P<0.01)。在2种模型中,与模型组比较,黄芪总苷56 mg/kg组小鼠肝质量和肝脏系数均降低(P<0.05,P<0.01),血清ALT、AST、ALP活性和TBA、胆红素等水平均降低(P<0.05,P<0.01),肝脏损伤明显改善,胶原沉积减少,胶原阳性面积和肝组织HYP水平均减少(P<0.05,P<0.01),肝组织α-SMA、Col1a1、Col4a1和TGF-β1表达降低(P<0.05,P<0.01),SIRT1表达升高(P<0.05,P<0.01)。结论56 mg/kg黄芪总苷可有效改善胆汁淤积性肝纤维化,其作用机制与促进SIRT1表达相关。AIM To investigate the effects of total astragalosides on cholestatic liver fibrosis in mice and the mechanism.METHODS Two models of cholestatic liver fibrosis were used,C57BL/6 mice underwent 4 weeks gavage of obeticholic acid and total astragalosides(112,56 mg/kg)starting from the fifth week of their 8-week 0.1%DDC feeding;Mdr2^(-/-)mice at 8 weeks old were given astragalosides(56,28 mg/kg)and obeticholic acid by gavage for 3 weeks,in contrast to those of the control group and the model group given the same volume of distilled water by gavage.The mice had detections of their liver mass and liver coefficient,serum liver function,liver histopathological changes and the expressions of liver fibrosis related indices detected after the administration.RESULTS Compared with the control groups,the DDC and Mdr2^(-/-)model groups displayed increased liver mass and liver coefficient(P<0.01),increased activities of serum ALT,AST and ALP,and levels of TBA and bilirubin(P<0.01),increased structural disorders,a larger number of inflammatory cells infiltration,collagen deposition in portal area,more collagen positive area and HYP level in liver tissue revealed by liver histopathology(P<0.01),increased hepaticα-SMA,Col1a1,Col4a1 and TGF-β1 expressions(P<0.01),and decreased SIRT1 expression(P<0.01).Compared with the model group,the groups intervened with 56 mg/kg total astragalosides demonstrated,decreased liver mass and liver coefficient(P<0.05,P<0.01);decreased activities of serum ALT,AST and ALP,and the levels of TBA and bilirubin(P<0.05,P<0.01);obviously improved liver injury,reduced collagen deposition,decreased positive area of collagen and the level of HYP in liver tissue(P<0.05,P<0.01);decreased hepatic expressions ofα-SMA,Col1a1,Col4a1 and TGF-β1(P<0.05,P<0.01),and increased SIRT1 expression(P<0.05,P<0.01).CONCLUSION 56 mg/kg astragalosides can effectively improve cholestatic hepatic fibrosis via SIRT1 expression activation.

关 键 词：黄芪总苷 胆汁淤积 肝纤维化 沉默信息调节因子1(SIRT1) 转化生长因子β(TGF-β) 

分 类 号：R285[医药卫生—中药学]