PPARα的激动可能与小檗碱的降脂作用有关
摘要
目的:
观察Ber对脂质代谢紊乱的防治作用,并探讨其降脂作用与PPARα之间的关系。
方法:
1.培养人肝癌细胞HepG2 ,给予不同浓度Ber(10~(-6)mol/l、3×10~(-6)mol/l、10~(-5)mol/l、3×10~(-5)mol/l、10~(-4)mol/l、3×10~(-4)mol/l),作用细胞24 h后应用RT-PCR观察对HepG2细胞PPARα及其调控基因CPTⅠA mRNA表达水平的影响,确定Ber作用的最佳浓度。然后用Ber最佳浓度作用HepG2细胞6 h、12 h、24 h、48 h和72 h后,应用RT-PCR观察对HepG2 CPTⅠA mRNA表达水平的影响,确定Ber最佳作用时间。
2.培养人肝癌细胞HepG2,给予Ber(3×10~(-5)mol/l) +或不+ MK886 (10~(-5)mol/l)和FF(2×10~(-5)mol/l)+或不+ MK886 (10~(-5)mol/l)分别作用24 h后,采用RT-PCR检测各用药组细胞CPTⅠA mRNA表达水平。
3.采用蛋白质免疫印迹法(Western blot)检测各用药组细胞CPTⅠA蛋白表达水平。
4.采用高脂加高胆固醇饲料,建立大鼠高脂模型。实验分5组:(1)对照组(普通饲料);(2)模型组(高脂加高胆固醇饲料);(3)Ber低剂量组(高脂加高胆固醇饲料+Ber 60 mg/kg);(4)Ber高剂量组(高脂加高胆固醇饲料+ Ber 300 mg/kg );(5)洛伐他汀组(高脂加高胆固醇饲料+70 mg/kg)。每组各8只大鼠。20周后尾部采血,用全自动生化分析仪测定血清胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白(LDL)、高密度脂蛋白(HDL),确定高脂模型建立,观察各组药物对大鼠血脂变化的影响。
5.采用RT-PCR检测各组动物肝脏PPARα和CPTⅠA mRNA表达水平。
6.采用Western blot检测各组动物CPTⅠA蛋白表达水平。
结果:
1. Ber显著呈浓度和时间依赖性促进CPTⅠA mRNA的表达,但是对PPARαmRNA表达没有显著影响。
2. Ber(3×10~(-5) mol/l)对CPTⅠA mRNA和蛋白表达有明显促进作用(P<0.01);PPARα特异激动剂FF(2×10~(-5) mol/l)也明显促进CPTⅠA mRNA和蛋白表达(P<0.01);PPARα特异拮抗剂MK-886预处理细胞后阻断了FF和Ber上述作用。
3. Ber 60 mg/kg和300 mg/kg每天给予明显降低高脂大鼠血浆TC、TG和LDL-C水平;其作用与洛伐他汀无显著差异。
4. Ber高、低剂量组明显促进HepG2 CPTⅠA mRNA和蛋白表达;但并不明显影响PPARαmRNA和蛋白表达;洛伐他汀对HepG2的PPARα和CPTⅠA mRNA和蛋白表达无明显影响。
结论:
Ber能显著降低高脂血症大鼠血浆TC和LDL水平;其作用原理可能与激动PPARα,由此促进以CPTⅠA为代表的,受PPARα调控的,涉及脂质代谢的基因表达有关。
Objective:
Investigate the effects of Ber on lipid metabolism disorder and its mechanism involving in PPARα.
Methods:
1. Human hepatoma cell line HepG2 was treated by Ber with various concentrations (10~(-6)mol/l,3×10~(-6)mol/l,10~(-5)mol/l,3×10~(-5)mol/l,10~(-4)mol/l,3×10~(-4)mol/l) for 24 h,the mRNA expressions of PPARαand its regulatory gene CPTⅠA in the cultured HepG2 cells were assayed by RT-PCR and 3×10~(-5)mol/l was ascertained as the optimal concentration. Then HepG2 cells was treated by Ber in optimal concentration for 6 h,12 h,24 h,48 h,and 72 h, respectively, the mRNA expressions of CPTⅠA was assayed by RT-PCR, and 24 h was ascertained as the optimal time.
2. HepG2 cells were treated by either Ber (3×10~(-5)mol/l) with or without MK886 (10~(-5)mol/l) or fenofibrate (2×10~(-5)mol/l) with or without MK886 (10~(-5)mol/l) for 24 h. RT-PCR and western-blot were used to evaluate the mRNA and protein expressions of CPTⅠA in HepG2 cells.
3. Hyperlipidemic rat model was induced by High fat and high cholesterol diet. All rats were randomly divided into 5 groups:(1)control group: Normal diet; (2)model group: High fat and high cholesterol diet;(3)Ber low dose group: High fat and high cholesterol diet +Ber 60 mg/kg(;4)Ber high dose group: High fat and high cholesterol diet +Ber 300 mg/kg; (5)lovastatin group: High fat and high cholesterol diet +lovastatin 70 mg/kg. The serum levels of cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL), and high density lipoprotein (HDL) were assayed by automatic biochemistry analyzer, and hyperlipidemic model and the effects of different drugs on rat lipid levels were identified.
4.RT-PCR were used to evaluate the mRNA expressions of PPARαand CPTⅠA in Rat Liver cells.
5.Western blot were used to evaluate the protein expression of CPTⅠA in Rat Liver cells.
Results:
1. Ber siginificantly promoted CPTⅠA mRNA expression of HepG2 cells in a concentration- and time-dependent manners(P<0.05,P<0.01), but had no effect on the expression of PPARαmRNA.
2. It was shown that Ber(3×10~(-5)mol/l) significantly promoted CPTⅠA mRNA and protein expressions(P<0.01);and a PPARαagonist, FF(2×10~(-5 )mol/l) also significantly promoted CPTⅠA mRNA and expressions (P<0.01); Specific PPARαantagonist MK886 could block the roles of FF and Ber mentioned above.
3. 20 weeks after Ber with either 60 mg/kg or 300 mg/kg was given to rats the TC, TG, and LDL-C levels of rat serum were significantly decreased with elevation of HDL-C, compared with model rats. Similar results were observed in lovastatin group.
4. The mRNA and protein expressions of CPTⅠA of both Ber 60 mg/kg and 300 mg/kg groups were higher than that of model group, and lower than that of control group(P<0.01), but no significant differences of the mRNA expressions of PPARαwere observed between Ber-treated groups and model group. The mRNA and protein expressions of CPTⅠA of lovastatin group hadn’t significant difference, compared with model group.
Conclusion:
Ber can significantly decrease the TC and LDL levels of serum from hyperlipidemic rats, the mechanism of which may be related to the expressions of genes (including CPTⅠA ) involved in the lipid metabolism and modulated by PPARα.
观察Ber对脂质代谢紊乱的防治作用,并探讨其降脂作用与PPARα之间的关系。
方法:
1.培养人肝癌细胞HepG2 ,给予不同浓度Ber(10~(-6)mol/l、3×10~(-6)mol/l、10~(-5)mol/l、3×10~(-5)mol/l、10~(-4)mol/l、3×10~(-4)mol/l),作用细胞24 h后应用RT-PCR观察对HepG2细胞PPARα及其调控基因CPTⅠA mRNA表达水平的影响,确定Ber作用的最佳浓度。然后用Ber最佳浓度作用HepG2细胞6 h、12 h、24 h、48 h和72 h后,应用RT-PCR观察对HepG2 CPTⅠA mRNA表达水平的影响,确定Ber最佳作用时间。
2.培养人肝癌细胞HepG2,给予Ber(3×10~(-5)mol/l) +或不+ MK886 (10~(-5)mol/l)和FF(2×10~(-5)mol/l)+或不+ MK886 (10~(-5)mol/l)分别作用24 h后,采用RT-PCR检测各用药组细胞CPTⅠA mRNA表达水平。
3.采用蛋白质免疫印迹法(Western blot)检测各用药组细胞CPTⅠA蛋白表达水平。
4.采用高脂加高胆固醇饲料,建立大鼠高脂模型。实验分5组:(1)对照组(普通饲料);(2)模型组(高脂加高胆固醇饲料);(3)Ber低剂量组(高脂加高胆固醇饲料+Ber 60 mg/kg);(4)Ber高剂量组(高脂加高胆固醇饲料+ Ber 300 mg/kg );(5)洛伐他汀组(高脂加高胆固醇饲料+70 mg/kg)。每组各8只大鼠。20周后尾部采血,用全自动生化分析仪测定血清胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白(LDL)、高密度脂蛋白(HDL),确定高脂模型建立,观察各组药物对大鼠血脂变化的影响。
5.采用RT-PCR检测各组动物肝脏PPARα和CPTⅠA mRNA表达水平。
6.采用Western blot检测各组动物CPTⅠA蛋白表达水平。
结果:
1. Ber显著呈浓度和时间依赖性促进CPTⅠA mRNA的表达,但是对PPARαmRNA表达没有显著影响。
2. Ber(3×10~(-5) mol/l)对CPTⅠA mRNA和蛋白表达有明显促进作用(P<0.01);PPARα特异激动剂FF(2×10~(-5) mol/l)也明显促进CPTⅠA mRNA和蛋白表达(P<0.01);PPARα特异拮抗剂MK-886预处理细胞后阻断了FF和Ber上述作用。
3. Ber 60 mg/kg和300 mg/kg每天给予明显降低高脂大鼠血浆TC、TG和LDL-C水平;其作用与洛伐他汀无显著差异。
4. Ber高、低剂量组明显促进HepG2 CPTⅠA mRNA和蛋白表达;但并不明显影响PPARαmRNA和蛋白表达;洛伐他汀对HepG2的PPARα和CPTⅠA mRNA和蛋白表达无明显影响。
结论:
Ber能显著降低高脂血症大鼠血浆TC和LDL水平;其作用原理可能与激动PPARα,由此促进以CPTⅠA为代表的,受PPARα调控的,涉及脂质代谢的基因表达有关。
Objective:
Investigate the effects of Ber on lipid metabolism disorder and its mechanism involving in PPARα.
Methods:
1. Human hepatoma cell line HepG2 was treated by Ber with various concentrations (10~(-6)mol/l,3×10~(-6)mol/l,10~(-5)mol/l,3×10~(-5)mol/l,10~(-4)mol/l,3×10~(-4)mol/l) for 24 h,the mRNA expressions of PPARαand its regulatory gene CPTⅠA in the cultured HepG2 cells were assayed by RT-PCR and 3×10~(-5)mol/l was ascertained as the optimal concentration. Then HepG2 cells was treated by Ber in optimal concentration for 6 h,12 h,24 h,48 h,and 72 h, respectively, the mRNA expressions of CPTⅠA was assayed by RT-PCR, and 24 h was ascertained as the optimal time.
2. HepG2 cells were treated by either Ber (3×10~(-5)mol/l) with or without MK886 (10~(-5)mol/l) or fenofibrate (2×10~(-5)mol/l) with or without MK886 (10~(-5)mol/l) for 24 h. RT-PCR and western-blot were used to evaluate the mRNA and protein expressions of CPTⅠA in HepG2 cells.
3. Hyperlipidemic rat model was induced by High fat and high cholesterol diet. All rats were randomly divided into 5 groups:(1)control group: Normal diet; (2)model group: High fat and high cholesterol diet;(3)Ber low dose group: High fat and high cholesterol diet +Ber 60 mg/kg(;4)Ber high dose group: High fat and high cholesterol diet +Ber 300 mg/kg; (5)lovastatin group: High fat and high cholesterol diet +lovastatin 70 mg/kg. The serum levels of cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL), and high density lipoprotein (HDL) were assayed by automatic biochemistry analyzer, and hyperlipidemic model and the effects of different drugs on rat lipid levels were identified.
4.RT-PCR were used to evaluate the mRNA expressions of PPARαand CPTⅠA in Rat Liver cells.
5.Western blot were used to evaluate the protein expression of CPTⅠA in Rat Liver cells.
Results:
1. Ber siginificantly promoted CPTⅠA mRNA expression of HepG2 cells in a concentration- and time-dependent manners(P<0.05,P<0.01), but had no effect on the expression of PPARαmRNA.
2. It was shown that Ber(3×10~(-5)mol/l) significantly promoted CPTⅠA mRNA and protein expressions(P<0.01);and a PPARαagonist, FF(2×10~(-5 )mol/l) also significantly promoted CPTⅠA mRNA and expressions (P<0.01); Specific PPARαantagonist MK886 could block the roles of FF and Ber mentioned above.
3. 20 weeks after Ber with either 60 mg/kg or 300 mg/kg was given to rats the TC, TG, and LDL-C levels of rat serum were significantly decreased with elevation of HDL-C, compared with model rats. Similar results were observed in lovastatin group.
4. The mRNA and protein expressions of CPTⅠA of both Ber 60 mg/kg and 300 mg/kg groups were higher than that of model group, and lower than that of control group(P<0.01), but no significant differences of the mRNA expressions of PPARαwere observed between Ber-treated groups and model group. The mRNA and protein expressions of CPTⅠA of lovastatin group hadn’t significant difference, compared with model group.
Conclusion:
Ber can significantly decrease the TC and LDL levels of serum from hyperlipidemic rats, the mechanism of which may be related to the expressions of genes (including CPTⅠA ) involved in the lipid metabolism and modulated by PPARα.
引文
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[2] Latruffe N, Vamecq J. Peroxisome proliferators and peroxisome proliferator- activated receptors (PPARs) as regulators of lipid metabolism[J]. Biochimie. 1997,79:81~94
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