新型PPARδ受体激动剂体外活性筛选及对高血脂金黄地鼠的调脂作用

发布时间：2018-11-17 08:17

【摘要】：对新型过氧化物酶体增殖物激活受体(peroxisome proliferator-activated receptors,PPARs)激动剂HS060098激活PPARα、PPARγ和PPARδ受体的活性进行筛选,并研究其对饮食性高脂血症金黄地鼠的血脂调节作用。首先,以肝癌HepG2细胞构建PPARs-荧光素酶基因报告系统,转染绿色荧光蛋白(green fluorescent protein,GFP)质粒作为内参,分别加入不同浓度的HS060098后继续培养24 h,通过检测荧光素酶的相对活性来评价HS060098对PPARα、PPARγ、PPARδ的激动活性;其次,以高脂饮食法复制金黄地鼠高脂血症模型,分别通过预防性给药与治疗性给药考察HS060098对高脂血症金黄地鼠血浆中总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)水平和脂肪指数的影响。体外研究结果显示,HS060098对PPARδ受体具有显著的激活作用,半数有效浓度(EC50)为0.01μmol·L~(-1);对PPARα和PPARγ并无明显的激活效应。体内研究结果显示,通过预防性给药和治疗性给药,与模型组比较,HS060098(5、10和20mg·kg~(-1))均可显著降低高脂血症金黄地鼠血浆中TC、TG、LDL-C水平和脂肪指数(P0.01,P0.05),升高HDL-C水平(P0.01,P0.05)。结果提示,HS060098具有较强的PPARδ激动活性,且对金黄地鼠实验性高脂血症具有显著的预防和治疗作用。
[Abstract]:The activities of PPAR 伪, PPAR 纬 and PPAR 未 receptors activated by HS060098, a novel peroxisome proliferator activated receptor (peroxisome proliferator-activated receptors,PPARs) agonist, were screened, and the effects of HS060098 on lipid regulation of dietary hyperlipidemia hamsters were studied. Firstly, PPARs- luciferase gene reporting system was constructed from HepG2 cells of liver cancer and transfected with green fluorescent protein (green fluorescent protein,GFP) plasmids as internal reference. After different concentrations of HS060098 were added, the cells were cultured for 24 h. The activation activity of HS060098 to PPAR 伪, PPAR 纬, PPAR 未 was evaluated by detecting the relative activity of luciferase. Secondly, the hyperlipidemia model of golden hamster was induced by high-fat diet. The effects of HS060098 on the serum total cholesterol (TC),) triglyceride (TG),) in hyperlipidemic hamsters were investigated by prophylactic and therapeutic administration, respectively. Effects of low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) levels and fat index. The results of in vitro study showed that HS060098 could activate PPAR 未 receptor significantly, half effective concentration (EC50) was 0. 01 渭 mol L ~ (-1), but there was no obvious activation effect on PPAR 伪 and PPAR 纬. The results of in vivo study showed that HS060098 (5n10 and 20mg kg~ (-1) could significantly reduce the TC,TG, in the plasma of hamsters with hyperlipidemia compared with the model group by prophylactic and therapeutic administration. The level of LDL-C and fat index (P0.01P 0.05) and the level of HDL-C increased (P0.01P 0.05). The results suggest that HS060098 has strong activation activity of PPAR 未 and has significant preventive and therapeutic effects on experimental hyperlipidemia in golden hamsters.
【作者单位】：温州医科大学附属第二临床医学院;浙江海正药业股份有限公司;浙江省台州市中心医院;
【分类号】：R965

【相似文献】