齐墩果酸对PCSK9mRNA表达及罗苏伐他汀降血脂作用的影响
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摘要
目的探讨齐墩果酸(oleanolic acid,OA)对大鼠肝脏、HepG2细胞PCSK9mRNA表达的影响,及OA与罗苏伐他汀(RSV)联用的降脂效果。方法 40只Wistar大鼠随机分为5组,每组8只。正常对照组以基础饲料喂养5周,高脂模型组、RSV组、OA组、OA联合RSV组以高脂饲料喂养5周,其中后3组从第4周开始分别给予RSV 10 mg/(kg·d)、OA 30 mg/(kg·d)、RSV 10 mg/(kg·d)+OA 30 mg/(kg·d)治疗2周。实验结束后,检测各组大鼠血清TC、TG、HDL-C、LDL-C水平,qPCR检测各组大鼠肝脏PCSK9mRNA和LDLRmRNA的表达。体外培养HepG2细胞,分为正常对照组,阳性对照组,RSV组(10μmol/L RSV),OA组(100μmol/L OA),OA联合RSV组(10μmol/L RSV+100μmol/L OA),其中后4组加入25 mg/L LDL。药物孵育24 h,qPCR检测各组HepG2细胞PCSK9mRNA和LDLRmRNA的表达。结果与高脂模型组比较,RSV组、OA组、OA联合RSV组的血清TC、TG、LDL-C水平均下降(P<0.05),其中OA联合RSV组下降更显著(P<0.05)。肝组织及HepG2细胞的qPCR结果显示:与高脂模型组或阳性对照组比较,RSV组PCSK9mRNA、LDLRmRNA表达增加(P<0.05),OA组PCSK9mRNA表达减少(P<0.05)、LDLRmRNA表达无明显变化(P>0.05);OA联合RSV组PCSK9mRNA、LDLRmRNA的表达介于RSV组与OA组两组间,差异均有统计学意义(P<0.05)。结论 OA可抑制肝脏、HepG2细胞PCSK9mRNA的表达,能拮抗RSV上调PCSK9mRNA表达的作用,与RSV联用能增强其降脂效果。
Objective To study the effects of oleanolic acid(OA) on the expression of PCSK9mRNA in liver of rats and HepG2 cells respectively and the lipid-lowering effects of OA combined with rosuvastatin(RSV). Methods 40 Wistar rats were randomly divided into 5 groups,8 in each group. The normal control group was fed with basic diet for 5 weeks, while the high-fat model group,RSV group,OA group and OA combined with RSV group were fed with high-fat diet for 5 weeks,among which the RSV 10 mg/(kg·d),OA 30 mg/(kg·d),RSV 10 mg/(kg·d)+OA 30 mg/(kg·d) were given to the latter three groups for 2 weeks from the forth week respectively.After the experiment,serum levels of TC,TG,HDL-C and LDL-C in rats of each group were detected,and the expression of PCSK9mRNA and LDLRmRNA in the livers of rats in each group were detected by qPCR.HepG2 cells were cultured in vitro and divided into normal control group, positive control group,RSV group(10 μmol/L RSV),OA group(100 μmol/L OA),OA combined with RSV group(10 μmol/L RSV+100 μmol/L OA). In the latter four groups,25 mg/L of LDL was added.After 24 h of drug incubation, the expression of PCSK9mRNA and LDLRmRNA in HepG2 cells was detected by qPCR. Results Compared with the high-fat model group,TC,TG and LDL-C levels of serum in the RSV group,OA group and OA combined with RSV group all decreased(P<0.05),among which the decrease was more significant in the OA combined with RSV group(P<0.05).qPCR results of liver tissues and HepG2 cells showed that,compared with high-fat model group or positive control group,PCSK9mRNA and LDLRmRNA expressions in RSV group increased(P<0.05),PCSK9mRNA expression decreased in OA group(P<0.05),and LDLRmRNA expression showed no significant changes(P>0.05).The expressions of PCSK9mRNA and LDLRmRNA in the OA combined RSV group were between the RSV group and the OA group,and the differences were statistically significant(P<0.05).Conclusion OA can inhibit the expression of PCSK9mRNA in liver and HepG2 cells,and antagonize the role of RSV in up-regulating the expression of PCSK9mRNA.Combined use of OA and RSV can enhance its lipid-lowering effect.
Objective To study the effects of oleanolic acid(OA) on the expression of PCSK9mRNA in liver of rats and HepG2 cells respectively and the lipid-lowering effects of OA combined with rosuvastatin(RSV). Methods 40 Wistar rats were randomly divided into 5 groups,8 in each group. The normal control group was fed with basic diet for 5 weeks, while the high-fat model group,RSV group,OA group and OA combined with RSV group were fed with high-fat diet for 5 weeks,among which the RSV 10 mg/(kg·d),OA 30 mg/(kg·d),RSV 10 mg/(kg·d)+OA 30 mg/(kg·d) were given to the latter three groups for 2 weeks from the forth week respectively.After the experiment,serum levels of TC,TG,HDL-C and LDL-C in rats of each group were detected,and the expression of PCSK9mRNA and LDLRmRNA in the livers of rats in each group were detected by qPCR.HepG2 cells were cultured in vitro and divided into normal control group, positive control group,RSV group(10 μmol/L RSV),OA group(100 μmol/L OA),OA combined with RSV group(10 μmol/L RSV+100 μmol/L OA). In the latter four groups,25 mg/L of LDL was added.After 24 h of drug incubation, the expression of PCSK9mRNA and LDLRmRNA in HepG2 cells was detected by qPCR. Results Compared with the high-fat model group,TC,TG and LDL-C levels of serum in the RSV group,OA group and OA combined with RSV group all decreased(P<0.05),among which the decrease was more significant in the OA combined with RSV group(P<0.05).qPCR results of liver tissues and HepG2 cells showed that,compared with high-fat model group or positive control group,PCSK9mRNA and LDLRmRNA expressions in RSV group increased(P<0.05),PCSK9mRNA expression decreased in OA group(P<0.05),and LDLRmRNA expression showed no significant changes(P>0.05).The expressions of PCSK9mRNA and LDLRmRNA in the OA combined RSV group were between the RSV group and the OA group,and the differences were statistically significant(P<0.05).Conclusion OA can inhibit the expression of PCSK9mRNA in liver and HepG2 cells,and antagonize the role of RSV in up-regulating the expression of PCSK9mRNA.Combined use of OA and RSV can enhance its lipid-lowering effect.
引文
[1] 第二次中国临床血脂控制状况多中心协作研究组.第二次中国临床血脂控制达标率及影响因素多中心协作研究[J].中华心血管病杂志,2007(5):420-427.
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[3] Khera A.Statins,Plasma PCSK9 Concentrations,and LDL Lowering[J].Clin Chem,2012,58(1):6-7.
[4] Seidah NG,Benjannet S,Wickham L,et al.The secretory proprotein convertase neural apoptosis-regulated convertase 1(NARC-1):liver regeneration and neuronal differentiation[J].Proc Natl Acad Sci USA,2003,100(3):928-933.
[5] Holla OL,Cameron J,Tveten K,et al.Role of the C-terminal domain of PCSK9 in degradation of the LDL receptors[J].J Lipid Res,2011,52(10):1787-1794.
[6] Gao D,Li Q,Li Y,et al.Antidiabetic and antioxidant effects of oleanolic acid from Ligustrum lucidum Ait in alloxan-induced diabetic rats[J].Phytother Res,2009,23(9):1257-62.
[7] 李雪飞,林红昱,廖芷余,等.齐墩果酸对HepG2细胞枯草溶菌素转化酶9表达的影响[J].湘南学院学报(医学版),2018,20(4):1-5.
[8] 叶明翔,裴建明.他汀类药物的功与过:降血脂药的使用新理念[J].心脏杂志,2010,22(3):433-436.
[9] Raal F,Panz V,Immelman A,et al.Elevated PCSK9 lev-els in untreated patients with heterozygous or homozygous familial hypercholesterolemia and the response to high-dose statin therapy[J].J Am Heart Assoc,2013,2(2):e000028.
[10] 欧露,麻燕妮,张彩平,等.烟酸通过下调 PCSK9的表达促进HepG2细胞摄取LDL-C[J].中国药理学通报,2017,33(2):243- 248.
[2] Jones P,Kafonek S,Laurora I,et al.Comparative dose efficacy study of atorvastatin versus simvastatin,pravastatin,lovastatin,and fluvastatin in patients with hypercholesterolemia(the CURVES study)[J].Am J Cardiol,1998,81(5):582-587.
[3] Khera A.Statins,Plasma PCSK9 Concentrations,and LDL Lowering[J].Clin Chem,2012,58(1):6-7.
[4] Seidah NG,Benjannet S,Wickham L,et al.The secretory proprotein convertase neural apoptosis-regulated convertase 1(NARC-1):liver regeneration and neuronal differentiation[J].Proc Natl Acad Sci USA,2003,100(3):928-933.
[5] Holla OL,Cameron J,Tveten K,et al.Role of the C-terminal domain of PCSK9 in degradation of the LDL receptors[J].J Lipid Res,2011,52(10):1787-1794.
[6] Gao D,Li Q,Li Y,et al.Antidiabetic and antioxidant effects of oleanolic acid from Ligustrum lucidum Ait in alloxan-induced diabetic rats[J].Phytother Res,2009,23(9):1257-62.
[7] 李雪飞,林红昱,廖芷余,等.齐墩果酸对HepG2细胞枯草溶菌素转化酶9表达的影响[J].湘南学院学报(医学版),2018,20(4):1-5.
[8] 叶明翔,裴建明.他汀类药物的功与过:降血脂药的使用新理念[J].心脏杂志,2010,22(3):433-436.
[9] Raal F,Panz V,Immelman A,et al.Elevated PCSK9 lev-els in untreated patients with heterozygous or homozygous familial hypercholesterolemia and the response to high-dose statin therapy[J].J Am Heart Assoc,2013,2(2):e000028.
[10] 欧露,麻燕妮,张彩平,等.烟酸通过下调 PCSK9的表达促进HepG2细胞摄取LDL-C[J].中国药理学通报,2017,33(2):243- 248.
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