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

发布时间：2017-12-28 02:31

本文关键词：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　出处：《中国药理学通报》2017年03期 　论文类型：期刊论文

【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。
[Abstract]:Objective To observe the acute hyperlipidemia model induced by intramuscular injection of chemical surface activator Triton WR-1399, investigate the relationship between aging and dose effect, and explore the mechanism of Triton WR-1399 induced hyperlipidemia animal model from gene level. Methods 0.4 g mice were treated with kg~ intramuscular injection mode (-1), 0.8 g - kg~ (-1) and 1.5 g kg~ (-1) Triton WR-1399, blood sampling time points of 24, 32, 48, 56, 72, 80 and 96 h, observe the 7 time points of mouse triglyceride (TG), cholesterol (TC), low density lipoprotein (LDL-C) and high density lipoprotein (HDL-C) changes; fluorescent quantitative PCR (RT-q PCR) method for the detection of lipoprotein lipase (LPL), cholesterol acyl transferase (LCAT), cholesterol 7- hydroxylase (CYP7A1), apolipoprotein AI (Apo AI), apolipoprotein (Apo B), low density lipoprotein receptor (LDLR), scavenger receptor class B type 1 (SRB1) and two HMG coenzyme A reductase (HMGCR) mRNA expression of lipid metabolism related genes of mRNA pathway. Based on the model replication method, the lipid regulating effect of bets and statins was studied to verify the stability of the model. The results of Triton WR-1399 (0.8 g - kg~ (-1), 1.5 g - kg~ (-1)) dose group TC, TG and LDL-C levels were significantly increased, the relative expression of LPL, LDLR, Apo, B and SRB1 genes were significantly decreased, the relative expression of HMGCR gene significantly increased; fenofibrate has obvious lipid-lowering effect on the acute model. Conclusion the mouse model of acute hyperlipidemia induced by intramuscular injection of 0.8 g kg~ (-1) Triton WR-1399 is stable, and can be used for screening lipid lowering drugs. The mechanism of its induced model may be related to inhibiting VLDL-C metabolic pathway and blocking the reverse cholesterol transport process. Mechanism based on this model, Liberia fenofibrate rosuvastatin showed more obvious lipid-lowering effect.
【作者单位】：广州中医药大学;广东省中医药工程技术研究院;广东省中医药研究开发重点实验室;广州中医药大学第二临床医学院;
【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)
【分类号】：R589.2;R-332
【正文快照】： R972.6;R977.6HMGCR;LPL;非诺贝特高脂血症(hyperlipidemia,HLP),即脂质代谢紊乱引起的多种脂质水平异常,是导致脂肪肝、动脉粥样硬化及心脑血管损害等多种疾病的重要因素[1]。因此,为筛选防治高脂血症的药物及其药效评价提供有效且稳定的动物模型显得尤为重要。Triton WR-139

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