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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(P<0.01,P<0.05),升高HDL-C水平(P<0.01,P<0.05)。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。
The activity of peroxisome proliferator-activated receptors (PPARs) agonist HS060098 on the activation of PPARα, PPARγ and PPARδ receptors was screened and its effects on diet-induced hyperlipidemia in golden hamster The role of lipid regulation. First, PPARs-luciferase reporter gene was constructed by HepG2 cells and transfected with green fluorescent protein (GFP) plasmid as an internal control. After adding different concentrations of HS060098 for 24 h, luciferase Relative activity to evaluate HS060098 on PPARα, PPARγ, PPARδ agonistic activity; Second, the high-fat diet to reproduce the golden hamster hyperlipidemia model, respectively, by prophylactic and therapeutic administration of HS060098 on hyperlipidemia (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) and fat index in golden hamster. In vitro studies show that HS060098 has a significant activation of PPARδ receptor, the median effective concentration (EC50) of 0.01μmol·L -1; PPARα and PPARγ no significant activation effect. In vivo studies showed that HS060098 (5, 10 and 20 mg · kg -1) significantly reduced the levels of TC in hyperlipidemic golden hamster, compared with model group, by prophylactic and therapeutic administration TG, LDL-C and fat index (P <0.01, P <0.05), and increased HDL-C level (P <0.01, P <0.05). The results suggest that HS060098 has a strong PPARδ agonistic activity, and has significant preventive and therapeutic effects on experimental hyperlipidemia in golden hamster.