Triton WR-1399通过影响VLDL-C代谢通路和RCT诱导急性HLP小鼠模型的研究  

Study on hyperlipidemia mice models induced by Triton WR-1399 via VLDL-C metabolic pathway and reverse cholesterol transport

作　　者：卓俊城 曾晓会 曾巧煌 陈玉兴 蔡大可 姚楠 甘海宁 张成哲 

机构地区：[1]广州中医药大学,广东广州510504 [2]广东省中医药工程技术研究院,广东广州510095 [3]广东省中医药研究开发重点实验室,广东广州510095 [4]广州中医药大学第二临床医学院,广东广州510120

出　　处：《中国药理学通报》2017年第3期433-439,共7页Chinese Pharmacological Bulletin

基　　金：广东省科技厅资助项目(No 2015A040404030,2014A070705014,2013B060300034);广东省中医药管理局资助项目(No 20151013,20152006,20161026,20141028)

摘　　要：目的观察肌肉注射化学表面活化剂Triton WR-1399诱导小鼠急性高脂血症模型,考察时效和量效关系,并从基因水平探讨Triton WR-1399诱发高脂血症动物模型的机制。方法用肌肉注射的方式分别给予小鼠0.4 g·kg^(-1),0.8 g·kg^(-1)和1.5 g·kg^(-1)的Triton WR-1399,取血时间点为24、32、48、56、72、80和96 h,观察这7个时间点小鼠甘油三酯(TG)、胆固醇(TC)、低密度脂蛋白(LDL-C)和高密度脂蛋白(HDL-C)的变化;采用荧光定量PCR(RT-q PCR)法检测脂蛋白脂肪酶(LPL),胆固醇脂酰转移酶(LCAT),胆固醇7-羟化酶(CYP7A1),载脂蛋白AI(Apo AI),载脂蛋白(Apo B),低密度脂蛋白受体(LDLR),B类Ⅰ型清道夫受体(SRB1)和羟甲基戊二酰辅酶A还原酶(HMGCR)的脂质代谢相关通路基因mRNA相对表达量变化。基于模型复制方法考察,研究贝特类和他汀类代表药物的调脂作用,验证模型的稳定性。结果 Triton WR-1399(0.8 g·kg^(-1),1.5 g·kg^(-1))剂量组的TC、TG和LDL-C水平明显升高,LPL、LDLR、Apo B和SRB1的基因相对表达明显降低,HMGCR的基因相对表达明显升高;非诺贝特对该急性模型有明显降脂作用。结论采用肌肉注射0.8 g·kg^(-1)Triton WR-1399所诱导的急性高脂血症小鼠模型稳定,可用于调脂药物筛选,其诱导模型的机制可能与抑制VLDL-C代谢通路和阻断胆固醇逆向转运过程有关。基于该模型的发病机制,非诺贝特比瑞舒伐他汀表现出更为明显的降脂作用。Aim Toinvestigatethetimeanddosage-dependent relationship in Triton WR-1399 -induced acute hyperlipidemia mice models and explore the underlying mechanism in gene rela-tiveexpression.Methods Miceweregivendifferentdosagesof Triton WR-1399（0. 4 g·kg-1 ,0. 8 g·kg-1 ,1. 5 g·kg-1 ） through im and blood was collected at different time（24 h,32 h, 48 h,56 h,72 h,80 h and 96 h）to observe the changes of TG, TC,LDL-C and HDL-C in HLP mice models.RT-qPCR was uti-lized to detect gene relative expression of LPL,LDLR,ApoA1 , ApoB,LCAT,SRB1,CYP7A1 and HMGCR.To verify stability of this model,fenofibrate and rosuvastatin were adapted to inves-tigate the mechanism of lipid regulation based on the exploration ofacuteHLPmicemodels.Results TritonWR-1399（0.8g· kg-1 ,1. 5 g·kg-1 ）could significantly reduce the level of TC,TG,LDL-C and enhance the content of HDL-C.In addition,it obviously inhibited the gene relative expression of LPL,LDLR, ApoB andSRB1 , while HMGCR was significantly enhanced. Fenofibrate showed noble hypolipidemic efficacy in this model. Conclusions Theeffectivetimerangeforscreeninglow-choles-terol is 24 h^32 h after intramuscular injection of Triton WR-1399（0. 8 g·kg-1 ）and the underlying mechanism is likely as-sociated with inhibition of metabolic pathway of VLDL-C and block of the reverse cholesterol transport.Based on the mecha-nism of acute HLP mice models,fenofibrate performs stronger hy-polipidemic efficacy than rosuvastatin.

关 键 词：TRITON WR-1399 高脂血症模型 基因表达 VLDL-C HMGCR LPL 非诺贝特 

分 类 号：R-332[医药卫生] R344