泊洛沙姆407诱发金黄地鼠脂质代谢紊乱模型及其初步机制

A dyslipidemia animal model induced by poloxamer 407 in golden hamsters and pilot study on the mechanism

采用泊洛沙姆(poloxamer 407,P-407)诱导金黄地鼠形成脂质代谢紊乱实验动物模型,并对其脂质代谢紊乱机制进行初步探讨;同时评价该模型对两类市售调脂药物的反应性。选择6周龄的雄性金黄地鼠腹腔注射P-407,首剂量为300 mg·kg-1,之后每72 h以200 mg·kg-1的维持剂量腹腔注射。与正常对照组相比,模型组血清中TG、TC、free-CHO、CE、FFA及apoB的水平均显著升高,LDL-C也有明显升高趋势;另外,模型组血清MDA和NO的含量显著增加。考察肝脏中脂质转运相关酶基因的转录水平变化,发现该模型肝脏中LCAT及SR-BⅠ的mRNA表达水平降低,HMG-CoA还原酶mRNA表达水平显著增加,以上3种酶的基因表达差异可能参与导致了该模型血脂代谢紊乱。在该脂质代谢紊乱模型中,分别给予非诺贝特(100 mg·kg-1)和阿托伐他汀(50 mg·kg-1),每日灌胃1次,连续2周,两种药物均可显著改善其血清脂质代谢紊乱和机体氧化应激及炎症状态。研究提示,雄性金黄地鼠通过连续多次腹腔注射P-407可形成持续性高血脂症,方法简便、形成时间短,且对药物的反应性良好。

The aim of this study is to establish a simple and stable model like poloxamer 407（P-407）-induced dyslipidemia of golden hamster model,and investigate the mechanism of lipid metabolism disturbance in this model.PPARα agonist and HMG-CoA reductase inhibitor were administrated to validate the efficacy on regulating lipid metabolism in the dyslipidemia golden hamster model.Six weeks male golden hamsters were chosen to inject P-407 intraperitoneally at a bolus dose of 300 mg-kg-1,an intermittent injection at a dose of 200 mg-kg-1 every 72 hours after the bolus.The results showed that P-407-induced golden hamster model characterized as increased serum triglyceride（TG）,total cholesterol（TC）,free cholesterol（free-CHO）,cholesteryl ester（CE）,free fatty acids（FFA） and apoB levels,and the hyperlipidemia state maintained at a stable level persistently.Meanwhile,augmented malondialdehyde（MDA） and nitric oxide（NO） level was observed.LCAT and SR-BⅠ mRNA levels in liver of model group were down-regulated（expression ratio is 0.426;0.783）,while HMG-CoA reductase mRNA level was up-regulated（expression ratio is 1.493） compared with those of the normal group.The serum cholesterol and triglyceride levels were significantly lower in P-407-induced dyslipidemia hamster model after treated with atorvastatin（Ato） at a dose of 50 mg-kg-1 or fenofibrate（Fen） at 100 mg-kg-1 for two weeks.These findings suggest that serum lipid distribution in dyslipidemia golden hamster is similar to that of human,and which may be relevant to the disturbance of the enzymes expression involved in lipid metabolism in liver.Results obtained from this study support the concept that dyslipidemia golden hamster may be an adequate animal model to evaluate the efficacy of lipid-lowering agents.