异甘草素改善2型糖尿病所致异常内质网应激机制研究  

Isoliquiritigenin alleviates abnormal endoplasmic reticulum stress induced by type 2 diabetes mellitus

作　　者：赖恺怡 丁文文 张佳瑜 杨晓雪 高文博 肖瑶[2] 刘颖 LAI Kai-yi;DING Wen-wen;ZHANG Jia-yu;YANG Xiao-xue;GAO Wen-bo;XIAO Yao;LIU Ying(School of Life Sciences,Beijing University of Chinese Medicine,Beijing 102488,China;School of Chinese Pharmacy,Beijing University of Chinese Medicine,Beijing 102488,China)

机构地区：[1]北京中医药大学生命科学学院,北京102488 [2]北京中医药大学中药学院,北京102488

出　　处：《药学学报》2025年第1期130-140,共11页Acta Pharmaceutica Sinica

摘　　要：异甘草素(isoliquiritigenin,ISL)是甘草中提取的查尔酮类化合物,具有抗糖尿病、抗癌及抗氧化等多种生物活性。课题组前期研究发现,ISL可降低2型糖尿病(type 2 diabetes mellitus,T2DM)小鼠的血糖水平,改善T2DM引起的糖脂代谢和能量代谢紊乱,本文拟进一步探究ISL缓解T2DM所致异常内质网应激(endoplasmic reticulum stress,ERS)的效果并解析其分子机制。体内实验采用8周龄SPF级雄性C57BL/6J小鼠,通过饲喂高脂高糖饮食结合腹腔注射链脲佐菌素(streptozotocin,STZ)构建T2DM动物模型,动物福利和实验过程均遵循北京中医药大学实验动物伦理委员会规定(批准号:BUCM-2022021503-1134);体外实验采用人肝癌HepG2细胞,以衣霉素(tunicamycin,TM)诱导ERS细胞模型。利用转录组测序分析ISL对T2DM小鼠肝脏基因转录水平的影响;采用实时荧光定量PCR(real-time quantitative polymerase chain reaction,RT-qPCR)检测ISL对ERS关键基因的调控作用;采用酶联免疫吸附法(enzyme-linked immunosorbent assay,ELISA)、蛋白质印迹法(Western blot,WB)以及免疫荧光技术检测ISL对ERS关键蛋白的调控作用。实验结果表明:ISL可显著下调ERS关键基因的表达,降低葡萄糖调节蛋白78(glucose-regulated protein 78,GRP78)的水平,并抑制蛋白激酶R样内质网激酶(protein kinase RNA-like endoplasmic reticulum kinase,PERK)的磷酸化,从而缓解T2DM所致异常ERS;同时,ISL可提高胰岛素受体底物(insulin receptor substrate,IRS)1和IRS2的蛋白水平,促进蛋白激酶B(protein kinase B,Akt)的磷酸化,改善胰岛素敏感性。综上,ISL可通过改善ERS和胰岛素敏感性,缓解T2DM相关症状。Isoliquiritigenin(ISL)is a chalcone compound isolated from licorice,known for its anti-diabetic,anti-cancer,and antioxidant properties.Our previous study has demonstrated that ISL effectively lowers blood glucose levels in type 2 diabetes mellitus(T2DM)mice and improves disturbances in glucolipid and energy metabolism induced by T2DM.This study aims to further investigate the effects of ISL on alleviating abnormal endoplasmic reticulum stress(ERS)caused by T2DM and to elucidate its molecular mechanisms.In vivo experiments were conducted using 8-week-old SPF male C57BL/6J mice.The T2DM animal model was established by high-fat and high-sugar diet combined with intraperitoneal injections of streptozotocin(STZ),in compliance with the ethical guidelines set by the Animal Welfare Committee of Beijing University of Chinese Medicine(approval number:BUCM-2022021503-1134).In vitro experiments employed human liver cancer HepG2 cells,which were induced with tunicamycin(TM)to establish the ERS cell model.Transcriptomic sequencing was used to analyze changes in gene expression in the liver samples of T2DM mice following ISL treatment.Real-time quantitative polymerase chain reaction(RT-qPCR)was employed to assess the regulatory effects of ISL on key ERS genes.Enzyme-linked immunosorbent assay(ELISA),Western blot(WB),and immunofluorescence techniques were used to evaluate ISL's effects on ERS-related proteins.Results indicate that ISL significantly downregulates the expression of ERS-related genes,reduces the level of glucose-regulated protein 78(GRP78),and inhibits the phosphorylation of protein kinase RNA-like endoplasmic reticulum kinase(PERK),thereby alleviating abnormal ERS induced by T2DM.Additionally,ISL increases the protein levels of insulin receptor substrate(IRS)1 and IRS2 and enhances the phosphorylation of protein kinase B(Akt),thereby improving insulin sensitivity.In conclusion,ISL is able to alleviate T2DM associated symptoms by improving abnormal ERS and enhancing insulin sensitivity.

关 键 词：异甘草素 2型糖尿病 内质网应激 胰岛素敏感性 糖代谢 

分 类 号：R966[医药卫生—药理学]