新型FGF21类似物DC2303对代谢相关脂肪性肝病的初步药效学评价  

Preliminary pharmacological effect of novel FGF21 analogue DC2303 on metabolic dysfunction-associated fatty liver disease

作　　者：沈蕾 邱云良 赵飞 李淋雨 SHEN Lei;QIU Yun-liang;ZHAO Fei;LI Lin-yu(School of Pharmacy,Anhui University of Traditional Chinese Medicine,Hefei 230013;InnoStar Biotechnology Nantong Co.,Ltd.,Nantong Jiangsu 226133;Yangtze Delta Drug Advanced Research Institute,Nantong Jiangsu 226133;Shanghai Innostar Bio-tech Co.,Ltd.,Shanghai 201203;China State Institute of Pharmaceutical Industry,Shanghai 201203)

机构地区：[1]安徽中医药大学药学院,合肥230013 [2]益诺思生物技术南通有限公司,江苏南通226133 [3]长三角药物高等研究院,江苏南通226133 [4]上海益诺思生物技术股份有限公司,上海201203 [5]中国医药工业研究总院,上海201203

出　　处：《中南药学》2025年第4期922-928,共7页Central South Pharmacy

基　　金：江苏省新药一站式高校非临床评价公共服务平台建设(No.BM2021002)。

摘　　要：目的探究DC2303对代谢相关脂肪性肝病(MAFLD)的治疗作用。方法①采用0.8 mmol·L^(-1)棕榈酸(PA)诱导HepG2细胞构建MAFLD模型对DC2303药效进行初步考察,Cell Titer-Glo发光法检测细胞活力;油红O染色分析细胞内脂滴蓄积程度;GPO-PAP酶法检测细胞内三酰甘油(TG)水平。②采用60%高脂饲料(HFD)诱导8周龄雄性db/db小鼠构建MAFLD模型对DC2303进行药效学评价,依据空腹血糖和体重,随机将动物分为Model组(PBS,10 mL·kg^(-1))、阳性对照组(Fc-FGF21,5、20 nmol·kg^(-1))、DC2303组(DC2303,5、20 nmol·kg^(-1)),定期监测小鼠体重、血糖和摄食量;GPO-PAP酶法检测小鼠血清TG、谷丙转氨酶(ALT)和谷草转氨酶(AST)水平;ELISA法检测小鼠血清胰岛素水平并计算胰岛素抵抗指数(HOMA-IR);HE染色和油红O染色对小鼠肝脏进行组织病理学分析。结果①体外药效评价:与Model组相比,DC2303显著降低细胞内TG水平,并且减少细胞内脂滴蓄积。②体内药效评价:与Model组相比,DC2303显著降低MAFLD小鼠的体重、摄食量、附睾脂肪重量、血糖和HOMA-IR;同时,显著降低肝重、肝体比、NAS评分、血清TG和ALT/AST水平,减少肝脏脂滴面积,并对MAFLD小鼠肝脏具有保护作用。此外,DC230320 nmol·kg^(-1)和Fc-FGF2120 nmol·kg^(-1)相比,DC2303在附睾脂肪重量、肝重、肝体比、NAS评分和逆转肝脂肪变性方面呈现优异的治疗作用。结论新型FGF21类似物DC2303可通过改善胰岛素抵抗、减轻肝脏损伤和逆转肝脂肪变性等多方面显著改善MAFLD模型。Objective To determine the therapeutic effect of DC2303 on metabolic dysfunction-associated fatty liver disease(MAFLD).Methods①HepG2 cells were treated with 0.8 mmol·L^(-1) palmitic acid(PA)to induce a MAFLD model,and the efficacy of DC2303 was preliminarily determine.Cell Titer-Glo luminescence assay was used to measure the cell viability,oil red O staining was performed to analyze lipid droplet accumulation in the cells,and GPO-PAP enzyme method to detect triglyceride(TG)levels in the cells.②A MAFLD model was established with 8-week-old male db/db mice fed with a 60%highfat diet(HFD)for pharmacological evaluation of DC2303.Based on fasting blood glucose and body weight,the mice were randomly assigned to a model group(PBS,10 mL·kg^(-1)),a positive control group(Fc-FGF21,5 and 20 nmol·kg^(-1)),and a DC2303 group(DC2303,5 and 20 nmol·kg^(-1)).The body weight,blood glucose,and food intake were regularly monitored,while the serum TG,alanine aminotransferase(ALT)and aspartate aminotransferase(AST)levels were detected by GPO-PAP enzyme method.The serum insulin levels were measured with ELISA and homeostasis model assessment of insulin resistance(HOMA-IR)conducted.HE staining and oil red O staining were performed for the histopathological analysis of mouse livers.Results①In the in vitro efficacy evaluation,DC2303 obviously reduced the intracellular TG levels and decreased the area of intracellular lipid droplet accumulation compared with those of the model group.②In the in vivo efficacy evaluation,DC2303 greatly reduced the body weight,food intake,epididymal fat weight,blood glucose,and HOMA-IR in the MAFLD mice compared with those of the model group.It also reduced the liver weight,liver-to-body ratio,NAS score,serum TG levels,serum ALT/AST levels,and liver lipid droplet area,and exhibited a protective effect on the liver of MAFLD mice.Additionally,DC2303 at 20 nmol·kg^(-1) demonstrated impressive therapeutic effects compared with Fc-FGF21 at 20 nmol·kg^(-1) in terms of epididymal fat weight,liver weight

关 键 词：代谢相关脂肪性肝病 成纤维细胞生长因子21 胰岛素抵抗 脂质蓄积 

分 类 号：R575.5[医药卫生—消化系统] R96[医药卫生—内科学]