药学学报, 2017, 52(1): 86-90
引用本文:
李露露, 艾进超, 李鸿炎, 郑晓鹤, 朱慧民. 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[J]. 药学学报, 2017, 52(1): 86-90.
LI Lu-lu, AI Jin-chao, LI Hong-yan, ZHENG Xiao-he, ZHU Hui-min. Impact of a noval PPARδ agonist on blood lipids in hyperlipidemic golden hamsters[J]. Acta Pharmaceutica Sinica, 2017, 52(1): 86-90.

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
李露露1, 艾进超2, 李鸿炎2, 郑晓鹤2, 朱慧民1,3
1. 温州医科大学附属第二临床医学院, 浙江 温州 325000;
2. 浙江海正药业股份有限公司, 浙江 台州 318000;
3. 浙江省台州市中心医院, 浙江 台州 318000
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 fluorescentprotein,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0.01 μmol·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。
关键词:    过氧化物酶体增殖物激活受体δ      报告基因      高脂血症      调脂作用     
Impact of a noval PPARδ agonist on blood lipids in hyperlipidemic golden hamsters
LI Lu-lu1, AI Jin-chao2, LI Hong-yan2, ZHENG Xiao-he2, ZHU Hui-min1,3
1. Second Clinical College of Wenzhou Medicine University, Wenzhou 325000, China;
2. Zhejiang Hisun Pharmaceutical Co., Ltd., Taizhou 318000, China;
3. Taizhou Central Hospital in Zhejiang Province, Taizhou 318000, China
Abstract:
The study was designed to explore the effects of HS060098 on activation of peroxisome proliferator-activated receptors (PPARα, γ and δ) and in the down-regulation of hyperlipidemia in golden hamster. Luciferase gene reporters of PPARα, PPARγ and PPARδ were constructed in HepG2 cells and the green fluorescent protein (GFP) was used as an internal reference. Transfected cells were then cultured with various concentrations of HS060098 for 24 h. The peroxisome proliferator-response element luciferase activity was determined by the dual-luciferase reporter gene assay system. To investigate the lipid-lowering effect of HS060098, hyperlipidemic golden hamsters fed by high-diet were administered orally with HS060098 through prophylactic and therapeutic approaches respectively. The levels of blood lipids such as total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) and fat index in hamsters were evaluated. The results showed that HS060098 was a potent activator of PPAR δ with a good selectivity and the median effective concentration (EC 50) is 0.01 μmol·L-1, while no obvious PPARα and PPARγ activation was observed. In the golden hamster, oral administration of HS060098 (5, 10, 20 mg·kg-1·d-1) for 2 weeks, led to a significant decrease the concentrations of plasma TC, TG, LDL-C and fat index (P<0.05 or P<0.01), whereas the contents of plasma HDL-C were increased significantly (P<0.05 or P<0.01). The data suggest that HS060098 is a novel PPAR δ agonist with a significant activity in the prevention and therapy of hyperlipemia in golden hamster.
Key words:    peroxisome proliferator-activated receptor delta    reporter gene    hyperlipidemia    blood lipids regulation   
收稿日期: 2016-07-24
DOI: 10.16438/j.0513-4870.2016-0730
通讯作者: 郑晓鹤,Tel:86-576-88828271,Fax:86-576-88828299,E-mail:zhengxh@hisunpharm.com;朱慧民,Tel:86-576-88526200,E-mail:htat@163.com
Email: zhengxh@hisunpharm.com;htat@163.com
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