苯扎贝特促进小鼠巨噬细胞胆固醇逆转运体内和体外研究
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摘要
背景
大量临床流行病学研究发现,人群中血浆高密度脂蛋白胆固醇(HDL-C)水平与冠心病发生率呈负相关,提示HDL具有抗动脉粥样硬化作用。胆固醇逆转运(RCT)是机体排出过多胆固醇的唯一途径,也是HDL抗动脉粥样硬化的重要机制之一。RCT指的是将外周组织细胞(包括巨噬细胞)游离胆固醇通过脂蛋白转运至肝脏,再通过肝脏排泄的过程。巨噬细胞是动脉粥样硬化病变的主要细胞成分,巨噬细胞过度荷脂转变为泡沫细胞,沉积于动脉壁形成早期的粥样斑块。因此,巨噬细胞RCT对动脉粥样硬化的发展起着最为关键的作用。三磷酸腺苷结合盒转运体超家族(ABCA1、ABCG1、ABCG5、ABCG8等)、B族清道夫受体Ⅰ(SR-BI)、胆固醇7α羟化酶(CYP7A1)等多种蛋白、受体、转运体参与RCT,并受肝X受体(LXRα)的调节。苯扎贝特是目前临床上常用的调血脂药物,可以明显降低甘油三酯(TG)和升高HDL-C。大规模临床研究证实苯扎贝特能有效延缓动脉斑块的形成,降低冠心病患者的临床终点事件发生的危险性。苯扎贝特抗动脉粥样硬化的机制除了其调节血脂如降低TG和升高HDL-C外,可能还具有调脂外的作用如抗炎、抗凝作用。对于RCT的作用的研究,苯扎贝特仅限于对RCT中转运蛋白如ABCA1、ABCG5的影响。然而,长期以来缺少对在体RCT的评价方法。本研究在Rader实验室的方法基础上建立了替代方法,观察苯扎贝特对巨噬细胞胆固醇逆转运体内、体外的影响,并探讨其可能的机制。
目的
观察苯扎贝特干预后小鼠血脂浓度变化,以及血清、肝脏及粪便中~3H-胆固醇占经腹腔注射~3H-胆固醇总量的百分比。研究苯扎贝特对小鼠体内巨噬细胞RCT的影响,苯扎贝特干预后小鼠血清及苯扎贝特对巨噬细胞内胆固醇流出的影响,探讨苯扎贝特调节巨噬细胞RCT的机制。
方法
以苯扎贝特(0.1%、0.25%、0.5%w/w)干预4周的C57BL/6J小鼠为模型,分别腹腔注射经乙酰化低密度脂蛋白(Ac-LDL)荷脂与~3H-胆固醇标记的巨噬细胞悬液,用液闪计数仪测定血清、肝脏、粪便中~3H-胆固醇的含量;收集0.25%苯扎贝特组小鼠血清孵育不同剂量的苯扎贝特(0、50、100、200μM)干预的RAW264.7巨噬细胞,测定细胞胆固醇流出;以RT-PCR方法检测肝组织CYP7A1、SR-BImRNA,肝脏和小肠ABCG5、LXRαmRNA,巨噬细胞SR-BI、ABCA1、ABCG1、LXRαmRNA的转录水平表达;再用Western-blot方法检测肝脏和小肠的ABCG5、LXRα,巨噬细胞ABCG1、LXRα的蛋白水平表达。
结果
1.小鼠经苯扎贝特(0.1%、0.25%、0.5%)干预4周后,血HDL-C升高,TG降低,这些作用呈剂量相关性趋势。0.5%苯扎贝特组HDL-C水平较对照组明显增高(P＜0.01),增幅为26.4%;TG水平较对照组明显降低(P＜0.01),降幅为34%。
2.采用不同剂量苯扎贝特(0.1%、0.25%、0.5%)干预小鼠,与对照组相比,血~3H-胆固醇含量显著增加,增幅分别为100%、131%、110%;肝脏~3H-胆固醇含量也显著增加,增幅分别为86.4%、52.3%、51.6%;粪便~3H-胆固醇含量同样显著增加,增幅分别为110%、140%、160%。
3.与对照组比较,苯扎贝特干预后的小鼠血清介导巨噬细胞内胆固醇流出明显增加(P＜0.05)。
4.苯扎贝特(0、50、100、200μM)呈剂量依赖性地增加血清诱导的巨噬细胞胆固醇流出率。
5.体外试验显示,苯扎贝特(0、50、100、200μM)呈剂量依赖性地上调巨噬细胞ABCA1、ABCG1、SR-BImRNA表达及ABCG1蛋白的表达量;并呈剂量依赖性地增加巨噬细胞LXRαmRNA及蛋白的表达量。
6.小鼠经苯扎贝特(0.1%,0.25%,0.5%)干预后,其肝脏SR-BI mRNA表达较对照组明显增加(P＜0.05)。
7.不同剂量苯扎贝特(0.1%,0.25%,0.5%)干预组小鼠肝脏、小肠ABCG5、LXRαmRNA表达与蛋白质表达较对照组明显增高(P＜0.05)。
8.各苯扎贝特(0.1%,0.25%,0.5%)干预组小鼠肝脏CYP7A1mRNA表达较对照组明显降低(P＜0.05)。
结论
1.苯扎贝特具有以下作用:
(1)降低小鼠血清TG,升高HDL-C。
(2)促进小鼠体内巨噬细胞相关的胆固醇逆转运。
(3)促进体外培养小鼠巨噬细胞胆固醇流出。
2.苯扎贝特促进小鼠巨噬细胞RCT的机制:
(1)通过增加ABCA1、ABCG1、SR-BI的表达,促进巨噬细胞胆固醇流出,可能与其上调LXRα表达有关。
(2)通过上调肝脏SR-BImRNA的表达,增加肝脏对胆固醇酯的选择性吸收;通过上调肝脏、小肠LXRα表达,增加ABCG5表达,促进胆固醇向胆汁中排泄,减少肠内胆固醇吸收。
(3)苯扎贝特促进巨噬细胞RCT可能与肝脏CYP7A1mRNA的表达无关。
Background
It has been found from numerous clinical epidemiological studies that the risk of developing coronary heart disease(CHD) is inversely related to high-density lipoprotein-cholesterol(HDL-C),which implies that HDL plays a role on the anti-atherosclerosis.Reverse cholesterol transport(RCT) is the only pathway from human body for excess cholesterol and one of the key mechanisms of HDL anti-atherosclerosis. RCT is a process that free cholesterol in peripheral cells,including macrophages,is transported to the liver in the form of HDL and excreted from liver.Macrophages are major cellular components of atherosclerotic lesions.Continuous accumulation of excess cholesterol in macrophages eventually leads to the formation of foam cells,which deposit on the arterial wall to form the characteristics of early atherosclerotic plaque. Therefore,Macrophages reverse cholesterol transport is the most crucial factor to atherosclerotic progress.Many proteins,receptors and transporters,such as ATP binding cassette transporter family(ABCA1, ABCG1,ABCG5 and ABCG8 etc.),scavenger receptor BI(SR-BI) and cholesterol 7alpha-hydroxylase(CYP7A1),all participate in RCT.And they are regulated by liver X receptorα(LXRα).Bezafibrate is a commonly used medicine that can efficiently lower triglyceride and increase HDL-C.It has proven from numerous clinical studies that bezafibrate significantly retards atherosclerosis progression and reduces the CHD death.Besides the effect of regulating the blood lipid,such as lowering triglyceride and increasing HDL-C,Bezafibrate has other effects, e.g.anti-inflammatory and anti-coagulation.A few studies indicate that the effect of bezafibrate on RCT is limited to affecting ABCA1 and ABCG5.However,no effective approach to assess RCT in vivo has been reported.In this work,an alternative approach has been developed on the basis of methods employed by Rader laboratory.We have evaluated the effect of bezafibrate on macrophages RCT in vivo and in vitro and discussed its possible mechanism.
Objectives
The objectives of this thesis are to investigate the effect of bezafibrate on macrophage RCT in mice in vivo and the effects of bezafibrate and mice serum on cholesterol efflux from macrophage in vivo,by determining the changes of lipid concentration and the ratio of 3H-cholesterol in serum,liver and feces to the total dose of 3H-cholesterol intraperitoneally injected after treating mice with bezafibrate,and to discuss the possible mechanisms of bezafibrate promotes macrophage reverse cholesterol transport.
Methods
After being treated with bezafibrate(0.1%,0.25%,0.5%W/W) for 4 weeks,C57BL/6 mice were injected intraperitoneally with ~3H-cholesterol-labeled and cholesterol-loaded(Ac-LDL) macrophages. The concentration of ~3H-tracer in samples of serum,liver and feces were determined by using liquid scintillation counter.Cholesterol efflux from 3H-cholesterol prelabled RAW264.7 macrophages incubated from mice serum with 0.25%bezafibrate in vitro was measured after being treated with different concentrations of bezafibrate.Reverse transcription polymerase chain reaction(RT-PCR) was used to evaluate mRNA expression of CYP7A1 and SR-BI of liver,ABCG5 and LXRαof liver and intestine as well as SR-BI,ABCA1,ABCG1 and LXRαof macrophage.And protein expression of ABCG5 and LXRαof liver as well as ABCG1 and LXRαof macrophage was evaluated with western-blot method.
Results
1.Being treated by bezafibrate(0.1%,0.25%,0.5%) for 4 weeks,the level of triglyceride(TG) and HDL-C was correlated to the bezafibrate dose.Compared to the control,HDL-C level increased (P＜0.01) by 26.4%,while TG level decreased(P＜0.01) by 34%in 0.5%bezafibrate group.
2.Compared to those in the control group,the ~3H-cholesterol levels in serum of the mice of treated group(0.1%,0.25%,0.5%) were significantly higher by 100%,131%and 110%,respectively. Similarly,the ~3H-cholesterol levels in liver and feces were significantly higher by 86.4%,52.3%and 51.6%,by 110%,140% and 160%,respectively.
3.Being treated with bezafibrate,Cholesterol efflux from macrophages mediated by the mice serum increased significantly,compared to those from the control group(P＜0.05).
4.Bezafibrate(0,50,100,200μM) dose-dependently promoted cholesterol efflux from macrophages mediated by the mice serum.
5.The experiements in vitro showed that the Bezafibrate(0,50,100, 200μM) with different concentrations dose-dependently increased the mRNA expression of ABCA1,ABCG1 and SR-BI as well as the protein expression of ABCG1,the mRNA and protein expression of LXRαof macrophages.
6.The SR-BImRNA expression of liver was dose-dependently upregulated in mice treated with different dosage of bezafibrate (0.1%,0.25%,0.5%),compared to those in control group(P＜0.05).
7.For treated group(0.1%,0.25%,0.5%),mRNA and protein expression of ABCG5 and LXRαof liver and intestine increased significant(P＜0.05),
8.For treated group(0.1%,0.25%,0.5%,the CYP7A1mRNA expression of mice liver were dose-dependently lower than those of control group(P＜0.05).
Conclusions
1.Bezafibrate has following effects:
1) Reduced the triglyceride(TG) level and increased the HDL-C level.
2) Promoted macrophages RCT in vivo in mice.
3) Promoted the cholesterol efflux from the cultured macrophages.
2.The key mechanisms of Bezafibrate promoting macrophages reverse cholesterol transport:
1) Bezafibrate increased the expression of ABCA1,ABCG1 and SR-BI to promote cholesterol efflux,which might be due to the up-regulation of LXRα.
2) Bezafibrate promoted macrophages reverse cholesterol transport in vivo possibly by upregulating the expression of SR-BImRNA to mediate the selective uptake of cholesteryl esters from HDL in the liver and through upregulating expression of ABCG5 of liver and intestine to promote cholesterol efflux via bile and to reduce uptake of cholesterol in intestine,which might be due to the up-regulation of LXRα.
3) Bezafibrate promoting macrophages reverse cholesterol transport in vivo had no relation to the expression of liver CYP7A1mRNA in mice.
大量临床流行病学研究发现,人群中血浆高密度脂蛋白胆固醇(HDL-C)水平与冠心病发生率呈负相关,提示HDL具有抗动脉粥样硬化作用。胆固醇逆转运(RCT)是机体排出过多胆固醇的唯一途径,也是HDL抗动脉粥样硬化的重要机制之一。RCT指的是将外周组织细胞(包括巨噬细胞)游离胆固醇通过脂蛋白转运至肝脏,再通过肝脏排泄的过程。巨噬细胞是动脉粥样硬化病变的主要细胞成分,巨噬细胞过度荷脂转变为泡沫细胞,沉积于动脉壁形成早期的粥样斑块。因此,巨噬细胞RCT对动脉粥样硬化的发展起着最为关键的作用。三磷酸腺苷结合盒转运体超家族(ABCA1、ABCG1、ABCG5、ABCG8等)、B族清道夫受体Ⅰ(SR-BI)、胆固醇7α羟化酶(CYP7A1)等多种蛋白、受体、转运体参与RCT,并受肝X受体(LXRα)的调节。苯扎贝特是目前临床上常用的调血脂药物,可以明显降低甘油三酯(TG)和升高HDL-C。大规模临床研究证实苯扎贝特能有效延缓动脉斑块的形成,降低冠心病患者的临床终点事件发生的危险性。苯扎贝特抗动脉粥样硬化的机制除了其调节血脂如降低TG和升高HDL-C外,可能还具有调脂外的作用如抗炎、抗凝作用。对于RCT的作用的研究,苯扎贝特仅限于对RCT中转运蛋白如ABCA1、ABCG5的影响。然而,长期以来缺少对在体RCT的评价方法。本研究在Rader实验室的方法基础上建立了替代方法,观察苯扎贝特对巨噬细胞胆固醇逆转运体内、体外的影响,并探讨其可能的机制。
目的
观察苯扎贝特干预后小鼠血脂浓度变化,以及血清、肝脏及粪便中~3H-胆固醇占经腹腔注射~3H-胆固醇总量的百分比。研究苯扎贝特对小鼠体内巨噬细胞RCT的影响,苯扎贝特干预后小鼠血清及苯扎贝特对巨噬细胞内胆固醇流出的影响,探讨苯扎贝特调节巨噬细胞RCT的机制。
方法
以苯扎贝特(0.1%、0.25%、0.5%w/w)干预4周的C57BL/6J小鼠为模型,分别腹腔注射经乙酰化低密度脂蛋白(Ac-LDL)荷脂与~3H-胆固醇标记的巨噬细胞悬液,用液闪计数仪测定血清、肝脏、粪便中~3H-胆固醇的含量;收集0.25%苯扎贝特组小鼠血清孵育不同剂量的苯扎贝特(0、50、100、200μM)干预的RAW264.7巨噬细胞,测定细胞胆固醇流出;以RT-PCR方法检测肝组织CYP7A1、SR-BImRNA,肝脏和小肠ABCG5、LXRαmRNA,巨噬细胞SR-BI、ABCA1、ABCG1、LXRαmRNA的转录水平表达;再用Western-blot方法检测肝脏和小肠的ABCG5、LXRα,巨噬细胞ABCG1、LXRα的蛋白水平表达。
结果
1.小鼠经苯扎贝特(0.1%、0.25%、0.5%)干预4周后,血HDL-C升高,TG降低,这些作用呈剂量相关性趋势。0.5%苯扎贝特组HDL-C水平较对照组明显增高(P＜0.01),增幅为26.4%;TG水平较对照组明显降低(P＜0.01),降幅为34%。
2.采用不同剂量苯扎贝特(0.1%、0.25%、0.5%)干预小鼠,与对照组相比,血~3H-胆固醇含量显著增加,增幅分别为100%、131%、110%;肝脏~3H-胆固醇含量也显著增加,增幅分别为86.4%、52.3%、51.6%;粪便~3H-胆固醇含量同样显著增加,增幅分别为110%、140%、160%。
3.与对照组比较,苯扎贝特干预后的小鼠血清介导巨噬细胞内胆固醇流出明显增加(P＜0.05)。
4.苯扎贝特(0、50、100、200μM)呈剂量依赖性地增加血清诱导的巨噬细胞胆固醇流出率。
5.体外试验显示,苯扎贝特(0、50、100、200μM)呈剂量依赖性地上调巨噬细胞ABCA1、ABCG1、SR-BImRNA表达及ABCG1蛋白的表达量;并呈剂量依赖性地增加巨噬细胞LXRαmRNA及蛋白的表达量。
6.小鼠经苯扎贝特(0.1%,0.25%,0.5%)干预后,其肝脏SR-BI mRNA表达较对照组明显增加(P＜0.05)。
7.不同剂量苯扎贝特(0.1%,0.25%,0.5%)干预组小鼠肝脏、小肠ABCG5、LXRαmRNA表达与蛋白质表达较对照组明显增高(P＜0.05)。
8.各苯扎贝特(0.1%,0.25%,0.5%)干预组小鼠肝脏CYP7A1mRNA表达较对照组明显降低(P＜0.05)。
结论
1.苯扎贝特具有以下作用:
(1)降低小鼠血清TG,升高HDL-C。
(2)促进小鼠体内巨噬细胞相关的胆固醇逆转运。
(3)促进体外培养小鼠巨噬细胞胆固醇流出。
2.苯扎贝特促进小鼠巨噬细胞RCT的机制:
(1)通过增加ABCA1、ABCG1、SR-BI的表达,促进巨噬细胞胆固醇流出,可能与其上调LXRα表达有关。
(2)通过上调肝脏SR-BImRNA的表达,增加肝脏对胆固醇酯的选择性吸收;通过上调肝脏、小肠LXRα表达,增加ABCG5表达,促进胆固醇向胆汁中排泄,减少肠内胆固醇吸收。
(3)苯扎贝特促进巨噬细胞RCT可能与肝脏CYP7A1mRNA的表达无关。
Background
It has been found from numerous clinical epidemiological studies that the risk of developing coronary heart disease(CHD) is inversely related to high-density lipoprotein-cholesterol(HDL-C),which implies that HDL plays a role on the anti-atherosclerosis.Reverse cholesterol transport(RCT) is the only pathway from human body for excess cholesterol and one of the key mechanisms of HDL anti-atherosclerosis. RCT is a process that free cholesterol in peripheral cells,including macrophages,is transported to the liver in the form of HDL and excreted from liver.Macrophages are major cellular components of atherosclerotic lesions.Continuous accumulation of excess cholesterol in macrophages eventually leads to the formation of foam cells,which deposit on the arterial wall to form the characteristics of early atherosclerotic plaque. Therefore,Macrophages reverse cholesterol transport is the most crucial factor to atherosclerotic progress.Many proteins,receptors and transporters,such as ATP binding cassette transporter family(ABCA1, ABCG1,ABCG5 and ABCG8 etc.),scavenger receptor BI(SR-BI) and cholesterol 7alpha-hydroxylase(CYP7A1),all participate in RCT.And they are regulated by liver X receptorα(LXRα).Bezafibrate is a commonly used medicine that can efficiently lower triglyceride and increase HDL-C.It has proven from numerous clinical studies that bezafibrate significantly retards atherosclerosis progression and reduces the CHD death.Besides the effect of regulating the blood lipid,such as lowering triglyceride and increasing HDL-C,Bezafibrate has other effects, e.g.anti-inflammatory and anti-coagulation.A few studies indicate that the effect of bezafibrate on RCT is limited to affecting ABCA1 and ABCG5.However,no effective approach to assess RCT in vivo has been reported.In this work,an alternative approach has been developed on the basis of methods employed by Rader laboratory.We have evaluated the effect of bezafibrate on macrophages RCT in vivo and in vitro and discussed its possible mechanism.
Objectives
The objectives of this thesis are to investigate the effect of bezafibrate on macrophage RCT in mice in vivo and the effects of bezafibrate and mice serum on cholesterol efflux from macrophage in vivo,by determining the changes of lipid concentration and the ratio of 3H-cholesterol in serum,liver and feces to the total dose of 3H-cholesterol intraperitoneally injected after treating mice with bezafibrate,and to discuss the possible mechanisms of bezafibrate promotes macrophage reverse cholesterol transport.
Methods
After being treated with bezafibrate(0.1%,0.25%,0.5%W/W) for 4 weeks,C57BL/6 mice were injected intraperitoneally with ~3H-cholesterol-labeled and cholesterol-loaded(Ac-LDL) macrophages. The concentration of ~3H-tracer in samples of serum,liver and feces were determined by using liquid scintillation counter.Cholesterol efflux from 3H-cholesterol prelabled RAW264.7 macrophages incubated from mice serum with 0.25%bezafibrate in vitro was measured after being treated with different concentrations of bezafibrate.Reverse transcription polymerase chain reaction(RT-PCR) was used to evaluate mRNA expression of CYP7A1 and SR-BI of liver,ABCG5 and LXRαof liver and intestine as well as SR-BI,ABCA1,ABCG1 and LXRαof macrophage.And protein expression of ABCG5 and LXRαof liver as well as ABCG1 and LXRαof macrophage was evaluated with western-blot method.
Results
1.Being treated by bezafibrate(0.1%,0.25%,0.5%) for 4 weeks,the level of triglyceride(TG) and HDL-C was correlated to the bezafibrate dose.Compared to the control,HDL-C level increased (P＜0.01) by 26.4%,while TG level decreased(P＜0.01) by 34%in 0.5%bezafibrate group.
2.Compared to those in the control group,the ~3H-cholesterol levels in serum of the mice of treated group(0.1%,0.25%,0.5%) were significantly higher by 100%,131%and 110%,respectively. Similarly,the ~3H-cholesterol levels in liver and feces were significantly higher by 86.4%,52.3%and 51.6%,by 110%,140% and 160%,respectively.
3.Being treated with bezafibrate,Cholesterol efflux from macrophages mediated by the mice serum increased significantly,compared to those from the control group(P＜0.05).
4.Bezafibrate(0,50,100,200μM) dose-dependently promoted cholesterol efflux from macrophages mediated by the mice serum.
5.The experiements in vitro showed that the Bezafibrate(0,50,100, 200μM) with different concentrations dose-dependently increased the mRNA expression of ABCA1,ABCG1 and SR-BI as well as the protein expression of ABCG1,the mRNA and protein expression of LXRαof macrophages.
6.The SR-BImRNA expression of liver was dose-dependently upregulated in mice treated with different dosage of bezafibrate (0.1%,0.25%,0.5%),compared to those in control group(P＜0.05).
7.For treated group(0.1%,0.25%,0.5%),mRNA and protein expression of ABCG5 and LXRαof liver and intestine increased significant(P＜0.05),
8.For treated group(0.1%,0.25%,0.5%,the CYP7A1mRNA expression of mice liver were dose-dependently lower than those of control group(P＜0.05).
Conclusions
1.Bezafibrate has following effects:
1) Reduced the triglyceride(TG) level and increased the HDL-C level.
2) Promoted macrophages RCT in vivo in mice.
3) Promoted the cholesterol efflux from the cultured macrophages.
2.The key mechanisms of Bezafibrate promoting macrophages reverse cholesterol transport:
1) Bezafibrate increased the expression of ABCA1,ABCG1 and SR-BI to promote cholesterol efflux,which might be due to the up-regulation of LXRα.
2) Bezafibrate promoted macrophages reverse cholesterol transport in vivo possibly by upregulating the expression of SR-BImRNA to mediate the selective uptake of cholesteryl esters from HDL in the liver and through upregulating expression of ABCG5 of liver and intestine to promote cholesterol efflux via bile and to reduce uptake of cholesterol in intestine,which might be due to the up-regulation of LXRα.
3) Bezafibrate promoting macrophages reverse cholesterol transport in vivo had no relation to the expression of liver CYP7A1mRNA in mice.
引文
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