目的 观察栀子苷对非酒精性脂肪性肝炎(NASH)大鼠的影响,基于蛋白质泛素化理论进一步探讨其可能机制.方法 运用高脂饮食16周建立大鼠NASH模型.将32只大鼠随机分为正常组、模型组、栀子苷组和盐酸吡格列酮组,每组8只.第9周起,正常组和模型组大鼠分别给予双蒸水10 mL/(kg·d)灌胃,栀子苷组和盐酸吡格列酮组分别给予60 mg/(kg·d)栀子苷溶液和10 mg/(kg·d)盐酸吡格列酮溶液,共干预8周.生化法检测肝组织甘油三酯(TG)含量、血清总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)的含量;HE染色观察肝组织病理学变化;ELISA法检测肝组织泛素特异性蛋白酶18(USP18)、去泛素化酶活性抑制转化生长因子-β激活激酶1(TAK1)、转化生长因子β活化激酶结合蛋白1(TAB1)表达水平.结果 与正常组比较,模型组大鼠显示出典型的NASH组织学特征,经过栀子苷干预后,肝细胞脂肪变性、炎症浸润减轻.与正常组比较,模型组大鼠体重、脂肪重量、肝湿重、肝指数、肝组织TG含量、血清TC、LDL-C含量均升高(P＜0.05),肝组织USP18、TAK1、TAB 1表达降低(P＜0.05).与模型组比较,栀子苷组大鼠脂肪重量、肝湿重、肝指数、肝组织TG含量、血清TC、LDL-C含量降低,肝组织USP18、TAK1、TAB1水平明显升高(P＜0.05);盐酸吡格列酮组大鼠脂肪重量、肝指数、肝组织TG与血清TC、LDL-C含量均降低(P＜0.05).结论 栀子苷能明显改善大鼠肝组织脂肪变性与炎症状态,升高肝组织USP18、TAK1、TAB1水平,其作用机制可能与调节蛋白质泛素化有关.
Objective To observe the effect of Geniposide on non-alcoholic steatohepatitis(NASH)rats,and to explore its mechanism based on protein ubiquitination.Methods NASH rat model was established by high-fat diet for 16 weeks.Thirty two rats were randomly divided into normal group,model group,Geniposid group and Pioglitazone hydrochloride group,with 8 rats in each group.The drug was administered at the 9th week,rats in normal group and model group were given 10 mL·kg-1·d-1 double distilled water by gavage,while those in Geniposide group and Pioglitazone hydrochloride group were respectively given 60 mg·kg-1·d-1 geniposide solution and 10 mg·kg-1·d-1 Pioglitazone hydrochloride solution,for a total of 8 weeks of intervention.The level of triglyceride(TG)in liver tissue and the contents of total cholesterol(TC),low-density lipoprotein cholesterol(LDL-C)in serum were detected by biochemical method.HE staining was used to observe the pathological changes of liver tissue.The activities of Ubquitin-specific protease 18(USP18),transforming growth factor-β activated kinase-1(TAK1)and TGF-beta-activated kinase 1 and MAP3 K7-binding protein 1(TAB1)were detected by ELISA.Results Compared with the normal group,typical histological characteristics of NASH was showed in the model group.After intervention,the steatosis and inflammatory infiltration of hepatocytes were reduced compared with the model group.Compared with the normal group,the weight,fat weight,liver wet weight,liver index,and TG content in the model group increased(P＜0.05),while the protein expression of USP18,TAK1 and TAB1 in liver tissue decreased(P＜0.05).Compared with the model group,the fat weight,liver wet weight,liver index,TG content in liver tissue,serum TC and LDL-C content decreased,while the protein expression of USP18,TAK1 and TAB1 in liver tissue significantly increased in Geniposide group(P＜0.05).The fat weight,liver index,TG content in liver tissue,serum TC and LDL-C content decreased in Pioglitazone hydrochloride group(P＜0.05).Conclusion Geniposide could improve the steatosis and inflammation of rat liver tissue,and increase the levels of USP18,TAK1 and TAB1 in rat liver tissue,and its mechanism might be related to the regulation of protein ubiquitination.
梁惠卿;郑晓婷;赖鹏华;许玲夏;刘垚昱;张绍良;周志佳;黄稚真;陈少东
厦门大学医学院(福建 361102)||厦门市中医院肝病中心(福建 361009)厦门市中医院肝病中心(福建 361009)厦门大学医学院(福建 361102)上海中医药大学附属曙光医院肝病科(上海 201203)福建中医药大学中西医结合学院(福建 351012)
栀子苷;非酒精性脂肪性肝炎;蛋白质泛素化;中药单体
Geniposide;non-alcoholic steatohepatitis;protein ubiquitination;Chinese medicine monomers
《中国中西医结合杂志》 2024 (004)
448-452 / 5
国家自然科学基金资助项目(No.82174141);国家中医药管理局青年岐黄学者支持项目(No.国中医药办人教函[2021]200号,[2022]256号);厦门市科技计划项目(No.3502 Z20224018)
10.7661/j.cjim.20231129.221
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