PGC-1α激动剂ZLN005减轻蛋氨酸胆碱缺乏饮食诱导的小鼠非酒精性脂肪性肝炎  

ZLN005,a PGC-1αagonist,attenuated MCD-induced non-alcoholic steatohepatitis in mice

作　　者：钟敏萱 蒋泞蔓 刘浩[2] 万敬员[2] 王璐[1] ZHONG Minxuan;JIANG Ningman;LIU Hao;WAN Jingyuan;WANG Lu(School of Basic Medicine,Yan′an University,Yanan 716000,China;Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology,Chongqing Medical University,Chongqing 400000,China)

机构地区：[1]延安大学基础医学院,陕西延安716000 [2]重庆医科大学重庆市生物化学与分子药理学重点实验室,重庆400016

出　　处：《延安大学学报（医学科学版）》2023年第2期20-25,共6页Journal of Yan'an University:Medical Science Edition

摘　　要：目的探讨过氧化物酶体增殖物激活受体共激活因子-1α(peroxisome proliferator activating receptor coactivator-1α,PGC-1α)激动剂2-(4-叔丁基苯基)苯并咪唑(2-(4-tert-butylphenyl)benzimidazole,ZLN005)对蛋氨酸胆碱缺乏饮食(cholinemethioninedeficientdiet,MCD)诱导的小鼠非酒精性脂肪性肝炎(non-alcoholic steatohepatitis,NASH)的作用及机制。方法用MCD饲料喂养小鼠构建NASH模型,给小鼠每日口服15 mg/mL的ZLN005,8周后检测小鼠血清丙氨酸氨基转移酶(alanine aminotransferase,ALT)、天门冬氨酸氨基转移酶(aspartate aminotransferase,AST)水平,对小鼠肝组织进行HE和油红O染色,丙二醛(malondialdehyde,MDA)和超氧化物歧化酶(superoxide dismutase,SOD)活性分析,RT-PCR检测肝组织白介素-1β(leucoides-1β)mRNA和肿瘤坏死因子(tumor necrosis factor alpha,TNF-α)mRNA的表达,Western blot检测小鼠肝组织内PGC-1α、血红素氧合酶1(heme oxygenase,HO-1)的蛋白表达。结果ZLN005处理,显著降低了血清ALT、AST水平,减轻了MCD诱导的NASH小鼠肝损伤、脂肪变性;减少了小鼠肝组织炎性细胞浸润;同时,ZLN005降低了IL-1β和TNF-α的mRNA水平;降低了肝脏MDA的含量,提高了SOD活性;上调了PGC-1α/HO-1的表达。结论ZLN005可缓解MCD诱导的NASH,其机制可能与激活PGC-1α/HO-1通路,发挥抗氧化应激和抗炎作用有关。Objective To investigate the peroxisome proliferator activating receptor coactivator-1α(PGC-1α)of 2-(4-tert-Butylphenyl)benzimidazole(ZLN005)on non-alcoholic steatohepatitis(NASH)induced by choline methionine deficient diet(MCD)in mice.Methods NASH model was established by feeding mice with MCD diet,and the mice were orally given 15 mg/mL ZLN005.Eight weeks later,the serum levels of alanine aminotransferase(ALT)and aspartate aminotransferase(AST)were detected,the liver tissues of mice were stained with HE and oil red O,and the activities of malondialdehyde(MDA)and superoxide dismutase(SOD)were analyzed.The expression of mRNA of leucoides-1βand tumor necrosis factor-α(TNF-α)in liver tissue were detected by RT-PCR.The protein expression of PGC-1αand heme oxygenase 1(HO-1)in mouse liver tissue were detected by western blot.Results ZLN005 treatment significantly reduced serum ALT and AST levels,reduced MCD induced liver injury and steatosis in NASH mice,and reduced inflammatory cell infiltration in liver tissue of mice.At the same time,ZLN005 decreased the mRNA levels of IL-1βand TNFα.The content of MDA in liver was decreased,and the activity of SOD was increased.Conclusion ZLN005 can alleviate MCD induced NASH,and its mechanism may be related to the activation of PGC-1α/HO-1 pathway which associated with antioxidant stress and anti-inflammatory effects.

关 键 词：ZLN005 非酒精性脂肪性肝病 PGC-1α/HO-1 

分 类 号：R362[医药卫生—病理学]