【摘要】：對(duì)新型過氧化物酶體增殖物激活受體(peroxisome proliferator-activated receptors,PPARs)激動(dòng)劑HS060098激活PPARα、PPARγ和PPARδ受體的活性進(jìn)行篩選,并研究其對(duì)飲食性高脂血癥金黃地鼠的血脂調(diào)節(jié)作用。首先,以肝癌HepG2細(xì)胞構(gòu)建PPARs-熒光素酶基因報(bào)告系統(tǒng),轉(zhuǎn)染綠色熒光蛋白(green fluorescent protein,GFP)質(zhì)粒作為內(nèi)參,分別加入不同濃度的HS060098后繼續(xù)培養(yǎng)24 h,通過檢測(cè)熒光素酶的相對(duì)活性來評(píng)價(jià)HS060098對(duì)PPARα、PPARγ、PPARδ的激動(dòng)活性;其次,以高脂飲食法復(fù)制金黃地鼠高脂血癥模型,分別通過預(yù)防性給藥與治療性給藥考察HS060098對(duì)高脂血癥金黃地鼠血漿中總膽固醇(TC)、甘油三酯(TG)、低密度脂蛋白膽固醇(LDL-C)、高密度脂蛋白膽固醇(HDL-C)水平和脂肪指數(shù)的影響。體外研究結(jié)果顯示,HS060098對(duì)PPARδ受體具有顯著的激活作用,半數(shù)有效濃度(EC50)為0.01μmol·L~(-1);對(duì)PPARα和PPARγ并無明顯的激活效應(yīng)。體內(nèi)研究結(jié)果顯示,通過預(yù)防性給藥和治療性給藥,與模型組比較,HS060098(5、10和20mg·kg~(-1))均可顯著降低高脂血癥金黃地鼠血漿中TC、TG、LDL-C水平和脂肪指數(shù)(P0.01,P0.05),升高HDL-C水平(P0.01,P0.05)。結(jié)果提示,HS060098具有較強(qiáng)的PPARδ激動(dòng)活性,且對(duì)金黃地鼠實(shí)驗(yàn)性高脂血癥具有顯著的預(yù)防和治療作用。
[Abstract]:The activities of PPAR 偽, PPAR 緯 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 偽, PPAR 緯, 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 偽 and PPAR 緯. 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.
【作者單位】： 溫州醫(yī)科大學(xué)附屬第二臨床醫(yī)學(xué)院;浙江海正藥業(yè)股份有限公司;浙江省臺(tái)州市中心醫(yī)院;
【分類號(hào)】：R965

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