ABCG1基因功能调节在动脉粥样硬化及巨噬细胞胆固醇外流中的作用研究
摘要
第一部分：ABCG1基因多态性对巨噬细胞胆固醇外流功能的影响及机制研究
胆固醇逆向转运是机体拮抗动脉粥样硬化的重要防御机制。巨噬细胞胆固醇外流是胆固醇逆向转运过程的起始,也是关键限速步骤。胆固醇外流是受到严格调控的主动转运过程。膜转运蛋白ABCG1在其中发挥重要作用,介导巨噬细胞内游离胆固醇和7-酮基胆固醇向胞外成熟高密度脂蛋白颗粒转运。特异性敲除ABCG1基因导致小鼠体内脂质代谢紊乱、外周组织内胆固醇沉积和大量泡沫细胞形成。目前研究显示多种因素可能影响ABCG1基因功能,包括基因多态性、microRNA及他汀类药物等。最近我们实验室对ABCG1基因单核苷酸多态性与冠心病发病的相关性研究显示,ABCG1启动子区-367G>A多态性与人群冠心病发生呈负相关,首次发现人ABCG1基因可能具有致动脉粥样硬化作用。据此,本研究将在这一发现的基础上更深入探讨ABCG1启动子区-367G>A多态性对基因表达与介导巨噬细胞胆固醇外流功能的影响,及其作用机制。
研究目的
1.调查ABCG1启动子区-367G>A多态性对ABCG1mRNA及蛋白表达的影响；调查ABCG1-367G>A多态性对ABCG1介导巨噬细胞胆固醇外流功能的影响；探讨相关发生机制；
2.评价ABCG1启动子区-367G>A多态性对转录因子结合及基因启动子转录活性影响；
3.调查ABCG1启动子区-367G>A多态性对凋亡相关基因表达的影响；
方法
1.采集健康受试者外周血,通过Ficoll密度梯度离心法分离人外周血单个核细胞(PBMCs),体外培养并诱导巨噬细胞分化；
2.通过荧光实时定量PCR及Western blotting技术检测PBMCs巨噬细胞中ABCG1和ABCA1表达水平；
3.通过测定巨噬细胞NBD胆固醇外流率,评价不同基因型PBMCs巨噬细胞胆固醇外流功能；
4.构建Luciferase报告基因载体,转染培养细胞后检测报告基因表达水平,评价ABCG1-367G>A位点改变对基因启动子转录活性的影响；
5.采用EMSA凝胶迁移实验分析ABCG1-367G>A位点改变对ABCG1启动子与转录因子结合的影响；
6.使用荧光实时定量PCR分析不同基因型PBMCs巨噬细胞中凋亡相关基因mRNA表达水平；
结果
1.体外培养HEK293T细胞中分别转染携带-367G或-367A序列的报告基因质粒载体,测定Luciferase报告基因表达水平。结果显示,基础状态-367A载体Luciferase报告基因活性显著低于-367G载体(12±1.5vs.22±2,n=4,p<0.01),LXR激动剂TO-901317刺激状态下-367A和-367G载体Luciferase报告基因活性均增加,但-367A报告基因活性显著低于-367G (21±2vs.32±3,n=4,p<0.01)。体外培养的HepG2细胞与THP-1细胞中,实验结果与HEK293T细胞结果相似；
2.将志愿者按照ABCG1-367G>A基因型不同分为三组：G/G型、G/A型和A/A型。与G/G型(n=25)相比,G/A型(0.87±0.04,n=22,p<0.01)和A/A型(0.41±0.10,n=5,p<0.01)单核巨噬细胞ABCG1mRNA表达明显降低；
3. PBMCs巨噬细胞中ABCG1蛋白水平在三组间比较：与G/G型(n=10)相比,G/A型(n=8,p<0.05)ABCG1表达明显降低,A/A型亦明显降低(p<0.01)：另外,膜转运蛋白ABCA1及SR-B1蛋白表达水平在三组之间未见明显差异；
4. ABCG1介导的巨噬细胞胆固醇外流率测定结果显示,与G/G组相比,G/A组与A/A组ABCG1介导的巨噬细胞胆固醇外流率均明显降低(p<0.01)：G/G组外流率为29.6%±2.1%,n=15；G/A组外流率24.9%±2.9%,n=10；A/A组外流率22.9%±3.8%,n=4。G/A组与A/A组外流率之间未见明显差异(p>0.05)；
5.EMSA实验中,分别使用包含位点-367G(G)或者-367A(A)的合成生物素标记探针与THP-1细胞核蛋白提取物反应,结果显示G探针区域可见一主要条带,条带强度随加入核蛋白量的增加而呈现增强,显示G探针可与核蛋白结合。而在A探针区域,未见明显结合条带,提示-367G>A位点改变影响DNA序列与核蛋白结合；
6. PBMCs巨噬细胞与50μg/ml ox-LDL预孵育48小时后通过荧光实时定量PCR检测各组细胞中凋亡相关基因Bok和Bid基因表达水平。结果显示与G/G组(n=8)相比,G/A组和A/A组(G/A+A/A:n=7,p<0.01) PBMCs细胞中Bok基因表达水平明显增高,Bid基因表达水平同样呈现增高(p<0.01)；
结论
1. ABCG1-367G>A位点改变削弱转录因子与ABCG1启动子结合作用,降低基因启动子转录活性,进而降低巨噬细胞中ABCG1表达水平及其介导的胆固醇外流功能。
2. ABCG1-367G>A位点改变上调巨噬细胞内凋亡相关基因表达水平,后者可能与巨噬细胞凋亡增加及动脉粥样硬化发生降低相关。
第二部分：他汀对ABCG1介导的巨噬细胞胆固醇外流的影响及机制研究
他汀类药物是目前临床应用最为广泛的一类调脂药物,1995年以来多项大规模临床研究结果显示他汀对于冠心病的一级、二级预防有明显作用,显著减少重要心血管事件及死亡率。其主要通过竞争性抑制3-羟基3-甲基戊二酰辅酶A (HMG-CoA)还原酶来减少胆固醇的生物合成,从而有效地降低机体总胆固醇和低密度脂蛋白胆固醇水平。除此以外,他汀类药物还存在改善内皮功能、减少斑块部位的炎症及氧化应激、稳定斑块及减少血栓形成等多种作用。最近研究显示,他汀影响膜蛋白ABCA1表达水平及其介导的巨噬细胞胆固醇外流过程。巨噬细胞胆固醇外流是胆固醇逆向转运过程中的关键限速步骤。机体通过胆固醇逆向转运将动脉壁过多的胆固醇运送回到肝脏,促进其经胆道排泄,从而拮抗动脉粥样硬化发生。ABCG1介导的胆固醇外流与ABCA1途径同为巨噬细胞胆固醇外流的两大重要途径。目前对于他汀类药物是否影响ABCG1介导的巨噬细胞胆固醇外流过程尚无报道。本研究拟通过评价他汀类药物对膜蛋白ABCG1表达及功能的影响,来全面了解他汀对巨噬细胞胆固醇外流过程的影响,并探讨其可能的作用机制。
研究目的
1.评价他汀类药物对巨噬细胞中ABCG1mRNA及蛋白表达水平的影响；
2.评价他汀类药物对ABCG1介导的巨噬细胞胆固醇外流功能的影响,并探讨可能的作用机制；
方法
1.分别使用不同浓度阿托伐他汀和辛伐他汀孵育体外培养的THP-1和PBMCs巨噬细胞。通过测定胆固醇外流率,评价他汀类药物对巨噬细胞胆固醇外流功能的影响；
2.通过荧光实时定量PCR以及免疫印迹Western blotting方法分别检测他汀作用前后细胞中ABCG1和ABCA1mRNA及蛋白表达水平的变化；
3.使用荧光实时定量PCR检测巨噬细胞中ABCG1两种亚型ABCG1-S和ABCG1-L在他汀作用前后mRNA水平变化；分别测定胆固醇外流率来评价ABCG1-S与ABCG1-L之间的功能差异；
4.通过生物素标记巨噬细胞膜表面蛋白,结合亲和素免疫共沉淀方法,分析他汀作用下巨噬细胞膜表面ABCG1蛋白表达变化；
5.使用LXR激动剂TO-901317联合他汀孵育THP-1巨噬细胞,测定药物作用前后巨噬细胞胆固醇外流率变化,并检测ABCG1两种亚型mRNA水平变化。比较联合使用LXR激动剂与单用他汀时,ABCG1基因表达和功能的改变。探讨相关作用机制。
结果
1.辛伐他汀孵育THP-1巨噬细胞24小时后,ABCG1介导的巨噬细胞胆固醇外流率显著降低,对照组外流率17.3%±0.8%,1μM辛伐他汀组降至13.5%±1.2%(n=4,p<0.01)。当使用10μM辛伐他汀孵育细胞,胆固醇外流率进一步下降至11.5%±0.6%(n=4,p<0.01)；使用阿托伐他汀孵育THP-1细胞24小时,ABCG1介导的胆固醇外流率亦呈显著降低,对照组外流率17.3%±0.8%,1μM阿托伐他汀组外流率降至14.4%±1.1%(n=4,p<0.01),10μM阿托伐他汀组外流率11.6%±1.4%(n=4,p<0.01);PBMCs巨噬细胞中实验结果与THP-1结果相似；
2.阿托伐他汀孵育细胞24小时,THP-1或PBMCs巨噬细胞内ABCG1蛋白表达未见明显改变；换用辛伐他汀孵育细胞,所观察到的结果与之类似；与ABCG1表达结果相对,他汀孵育24小时后THP-1或PBMCs巨噬细胞中ABCA1蛋白水平呈现明显降低,显示他汀对两种膜转运蛋白表达可能存在不同作用；
3.阿托伐他汀10μM或辛伐他汀10μM孵育细胞24小时,THP-1巨噬细胞膜表面的ABCG1表达水平未见明显改变,说明他汀并没有影响ABCG1在巨噬细胞膜表面的表达；
4.他汀孵育THP-1细胞24小时后,使用荧光实时定量PCR检测细胞中ABCG1两种亚型-ABCG1-S和ABCG1-L mRNA表达水平,结果显示1μM辛伐他汀组ABCG1-S/ABCG1-L mRNA比值从孵育前1.4±0.17降为0.7±0.13(n=4,p<0.01),10μM辛伐他汀组降为0.14±0.03(n=4,p<0.01)；而10μM阿托伐他汀孵育24小时后ABCG1-S/ABCG1-L mRNA比值降为0.24±0.05(n=4,p<0.01)。表明他汀类药物显著影响ABCG1两种亚型的表达水平；
5.他汀联合TO-901317组与单用他汀组相比,ABCG1-S/ABCG1-L mRNA表达比值显著增加；提示小剂量TO-901317(lnM)能够拮抗他汀所导致ABCG1亚型表达变化；
6.巨噬细胞胆固醇外流率测定结果显示,单用10μM辛伐他汀组胆固醇外流率为12.4%±1.2%,联用1nM TO-901317后胆固醇外流率增至16%±2.5%；单用10μM阿托伐他汀组胆固醇外流率为11.3%±0.5%,联用1nM TO-901317后胆固醇外流率增至15.2%±1.5%(n=4p<0.05)；提示小剂量TO-901317能够改善他汀引起的ABCG1胆固醇外流率降低。
结论
1.阿托伐他汀和辛伐他汀降低ABCG1介导的巨噬细胞胆固醇外流功能。其作用可能通过LXR依赖性方式进行；
2.他汀作用不改变ABCG1,总蛋白表达水平,但是改变了具有功能差异的两种ABCG1蛋白亚型在巨噬细胞中的表达比例,从而影响ABCG1总体功能,这可能代表了ABCG1基因一种新的功能调节方式；
3.他汀与LXR激动剂联合使用可能能够减少他汀类药物影响巨噬细胞胆固醇外流的副作用,从而增加临床获益。
Part Ⅰ
Background:
Macrophage cholesterol efflux is the initial step of reverse cholesterol transport, and provides protection against atherosclerosis. Lipid transporters ABCA1and ABCG1are essential components of macrophage cholesterol efflux, and play important but different roles in this process. Both in vitro and in vivo studies show that ABCA1functions in transporting cellular cholesterol from macrophage to lipid-poor apoA-1lipoprotein, whereas ABCG1transports cholesterol to mature HDL. Although studies have demonstrated anti-atherosclerosis effect of ABCA1, functional role of ABCG1in atherosclerosis remains controversial, mostly because of inconsistent results from animal studies. Recently, our lab performed an association study on ABCG1gene polymorphisms with coronary artery disease in humans. We found that human ABCG1-367G>A polymorphism located in the gene promote region was significantly associated with decreased risk for coronary artery disease and myocardial infarction. For the first time, our findings showed that ABCG1gene may promote development of atherosclerosis in humans. In this project, we further investigate whether the ABCG1genetic variant may alter the gene function, and explore the underlying mechanisms.
Objective:
1. To determine if ABCG1-367G>A polymorphism have an influence on the gene expression.
2. To evaluate if ABCG1-367G>A polymorphism have an influence on function of ABCG1-mediated cholesterol efflux.
3. To determine if ABCG1-367G>A polymorphism impair transcription factor binding and promoter activity.
Methods and Results:
1. Peripheral blood mononuclear cells were isolated from healthy subjects through Ficoll-Paque density gradient centrifugation and differentiated into macrophages using human macrophage colony-stimulating factor. We measured ABCG1mRNA level in macrophages from human subjects with different genotypes for ABCG1-367G>A using quantitative real-time PCR. Our results showed that ABCG1mRNA expression was significantly lower in macrophages from subjects with AA genotype than that in subjects with GG genotype (0.41±0.10of A/A, n=5; vs. G/G, n=25; p<0.01). ABCG1mRNA expression was also decreased in subjects with G/A genotype (0.87±0.04, n=22, p<0.01).
2. Through Western blot analysis, ABCG1protein level appeared significantly lower in macrophages from A/A subjects compared to that of G/G subjects (p<0.01). G/A subjects also showed a significantly lower ABCG1protein level compared to G/G subjects (p<0.05). On the other hand, ABCA1and SR-B1protein levels showed no significant difference between G/G, G/A and A/A subject groups.
3. We evaluate effect of ABCG1-367G>A polymorphism on the gene function by measuring ABCG1-mediated cholesterol efflux. The results showed that percentage cholesterol efflux of macrophages from A/A subjects (22.9%±3.8%, n=4) was lower than that of macrophages from either G/G (29.6%±2.1%, n=15, p<0.01) or G/A subjects (24.9%±2.9%, n=10,p<0.01). There was no significant difference between G/G and G/A subjects (p>0.05).
4. To examine whether the ABCG1-367G>A affect promoter transcriptional activity, we measured luciferase activity of ABCG1promoter construct containing the substitution. Our results showed that relative luciferase activity of p-A construct was significantly lower than that of wild-type p-G construct in HEK293T cells under either basal or TO-901317activated conditions. The results were confirmed in another two different cell lines, HepG2and THP-1cells.
5. We performed electrophoretic mobility shift assay and evaluated whether ABCG1-367G>A polymorphism may affect specific transcription factor binding. The results showed that one major DNA-protein complex was detected using the probe corresponding to the G allele, and its band intensity was markedly reduced in the presence of unlabelled G allele. There was no major band detected in the assay using the A allele probe.
6. We examined mRNA expressions of proapoptotic genes using quantitative real-time PCR. The results showed that bok mRNA level was significantly increased in macrophages from A/A and G/A subjects compared to that of G/G subjects. The bid mRNA level was also increased in A/A and G/A macrophages compared to that of G/G macrophages.
Conclusion:
The ABCG1-367G>A variant impaired transcription factor binding of the promoter and decreased its transcriptional activity. The genetic variant has an allele-specific effect on ABCG1gene expression and function in human macrophages, which provide evidence of a genotypic effect on atherosclerosis.
Part II
Background:
Statins are competitive inhibitors for3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-controlling enzyme in cholesterol synthesis. They are the most widely used cholesterol-lowering agents for lowering low-density lipoprotein (LDL) cholesterol concentration and for prevention of coronary artery disease. They reduce LDL-cholesterol concentration through the blockade of mevalonate pathway, the metabolic pathway that produces cholesterol, and the increases of LDL catabolism. Besides the effects on lowering LDL-cholesterol, statins showed pleiotropic effects including improving endothelial function, enhancing the stability of atherosclerotic plaques, decreasing oxidative stress and inflammation, and inhibiting the thrombogenic response. In addition, recent studies show that statins treatment may have influence on macrophage cholesterol efflux. Statins reduce ABCA1expression and ABCA1-mediated cholesterol efflux in macrophages. While statins effect on ABCG1, another important lipid transporter for macrophage cholesterol efflux, is still unclear. Here, we investigated statins effect on expression and functionality of ABCG1in human macrophages, and explore the underlying mechanism.
Objective:
1. To determine statins effect on ABCG1expression level in human macrophages.
2. To examine statins effect on ABCG1function, and explore the underlying mechanism.
Methods and Results:
Statins treatment significantly decreased ABCG1-mediated cholesterol efflux in human macrophages (From33.8%±2.8%of control to22.9%±1.7%of10μM simvastatin; or to23.3%±3.3%of10μM atorvastatin,p<0.01, n=4), whereas the protein expression of ABCG1remained unaltered on statins. The cell surface expression of ABCG1was also unaltered on statins. Further analysis revealed that two major ABCG1isoforms responded to statins differently. The expression of ABCG1-S,which exhibited higher activity in cholesterol efflux than that of ABCG1-L, was significantly decreased on statins compared to increased expression of ABCG1-L. The mRNA ratio of ABCG1-S/ABCG1-L was significantly decreased in THP-1cells under either1μM simvastatin (1.4±0.17of control to0.69±0.06of1μM simvastatin, n=4,p<0.01), or1μM atorvastatin (0.7±0.13,/p<0.01). Further changes on ABCG1-S/ABCG1-L ratio were observed under either10μM simvastatin (0.14±0.03, n=4, p<0.01), or10μM atorvastatin (0.24±0.05, n=4, p<0.01). Similar results were observed in PBMCs. The results suggested that the proportion change of ABCG1isoforms expressions could contribute to reduced ABCG1functionality under statins treatment. The statins effects on ABCG1isoforms expression and functionality was reversed by low-dose LXR agonist, TO-901317, indicating that statins down-regulation of ABCG1functionality was likely through LXR dependent pathway.
Conclusion:
In conclusion, simvastain and atorvastain decreased ABCG1-mediated cholesterol efflux in human macrophages without alteration of total ABCG1protein level. The proportion change of ABCG1isoforms expressions may be involved in the down-regulation of ABCG1functionality by statins, which provided a novel mechanism for the regulation of ABCG1function.
胆固醇逆向转运是机体拮抗动脉粥样硬化的重要防御机制。巨噬细胞胆固醇外流是胆固醇逆向转运过程的起始,也是关键限速步骤。胆固醇外流是受到严格调控的主动转运过程。膜转运蛋白ABCG1在其中发挥重要作用,介导巨噬细胞内游离胆固醇和7-酮基胆固醇向胞外成熟高密度脂蛋白颗粒转运。特异性敲除ABCG1基因导致小鼠体内脂质代谢紊乱、外周组织内胆固醇沉积和大量泡沫细胞形成。目前研究显示多种因素可能影响ABCG1基因功能,包括基因多态性、microRNA及他汀类药物等。最近我们实验室对ABCG1基因单核苷酸多态性与冠心病发病的相关性研究显示,ABCG1启动子区-367G>A多态性与人群冠心病发生呈负相关,首次发现人ABCG1基因可能具有致动脉粥样硬化作用。据此,本研究将在这一发现的基础上更深入探讨ABCG1启动子区-367G>A多态性对基因表达与介导巨噬细胞胆固醇外流功能的影响,及其作用机制。
研究目的
1.调查ABCG1启动子区-367G>A多态性对ABCG1mRNA及蛋白表达的影响；调查ABCG1-367G>A多态性对ABCG1介导巨噬细胞胆固醇外流功能的影响；探讨相关发生机制；
2.评价ABCG1启动子区-367G>A多态性对转录因子结合及基因启动子转录活性影响；
3.调查ABCG1启动子区-367G>A多态性对凋亡相关基因表达的影响；
方法
1.采集健康受试者外周血,通过Ficoll密度梯度离心法分离人外周血单个核细胞(PBMCs),体外培养并诱导巨噬细胞分化；
2.通过荧光实时定量PCR及Western blotting技术检测PBMCs巨噬细胞中ABCG1和ABCA1表达水平；
3.通过测定巨噬细胞NBD胆固醇外流率,评价不同基因型PBMCs巨噬细胞胆固醇外流功能；
4.构建Luciferase报告基因载体,转染培养细胞后检测报告基因表达水平,评价ABCG1-367G>A位点改变对基因启动子转录活性的影响；
5.采用EMSA凝胶迁移实验分析ABCG1-367G>A位点改变对ABCG1启动子与转录因子结合的影响；
6.使用荧光实时定量PCR分析不同基因型PBMCs巨噬细胞中凋亡相关基因mRNA表达水平；
结果
1.体外培养HEK293T细胞中分别转染携带-367G或-367A序列的报告基因质粒载体,测定Luciferase报告基因表达水平。结果显示,基础状态-367A载体Luciferase报告基因活性显著低于-367G载体(12±1.5vs.22±2,n=4,p<0.01),LXR激动剂TO-901317刺激状态下-367A和-367G载体Luciferase报告基因活性均增加,但-367A报告基因活性显著低于-367G (21±2vs.32±3,n=4,p<0.01)。体外培养的HepG2细胞与THP-1细胞中,实验结果与HEK293T细胞结果相似；
2.将志愿者按照ABCG1-367G>A基因型不同分为三组：G/G型、G/A型和A/A型。与G/G型(n=25)相比,G/A型(0.87±0.04,n=22,p<0.01)和A/A型(0.41±0.10,n=5,p<0.01)单核巨噬细胞ABCG1mRNA表达明显降低；
3. PBMCs巨噬细胞中ABCG1蛋白水平在三组间比较：与G/G型(n=10)相比,G/A型(n=8,p<0.05)ABCG1表达明显降低,A/A型亦明显降低(p<0.01)：另外,膜转运蛋白ABCA1及SR-B1蛋白表达水平在三组之间未见明显差异；
4. ABCG1介导的巨噬细胞胆固醇外流率测定结果显示,与G/G组相比,G/A组与A/A组ABCG1介导的巨噬细胞胆固醇外流率均明显降低(p<0.01)：G/G组外流率为29.6%±2.1%,n=15；G/A组外流率24.9%±2.9%,n=10；A/A组外流率22.9%±3.8%,n=4。G/A组与A/A组外流率之间未见明显差异(p>0.05)；
5.EMSA实验中,分别使用包含位点-367G(G)或者-367A(A)的合成生物素标记探针与THP-1细胞核蛋白提取物反应,结果显示G探针区域可见一主要条带,条带强度随加入核蛋白量的增加而呈现增强,显示G探针可与核蛋白结合。而在A探针区域,未见明显结合条带,提示-367G>A位点改变影响DNA序列与核蛋白结合；
6. PBMCs巨噬细胞与50μg/ml ox-LDL预孵育48小时后通过荧光实时定量PCR检测各组细胞中凋亡相关基因Bok和Bid基因表达水平。结果显示与G/G组(n=8)相比,G/A组和A/A组(G/A+A/A:n=7,p<0.01) PBMCs细胞中Bok基因表达水平明显增高,Bid基因表达水平同样呈现增高(p<0.01)；
结论
1. ABCG1-367G>A位点改变削弱转录因子与ABCG1启动子结合作用,降低基因启动子转录活性,进而降低巨噬细胞中ABCG1表达水平及其介导的胆固醇外流功能。
2. ABCG1-367G>A位点改变上调巨噬细胞内凋亡相关基因表达水平,后者可能与巨噬细胞凋亡增加及动脉粥样硬化发生降低相关。
第二部分：他汀对ABCG1介导的巨噬细胞胆固醇外流的影响及机制研究
他汀类药物是目前临床应用最为广泛的一类调脂药物,1995年以来多项大规模临床研究结果显示他汀对于冠心病的一级、二级预防有明显作用,显著减少重要心血管事件及死亡率。其主要通过竞争性抑制3-羟基3-甲基戊二酰辅酶A (HMG-CoA)还原酶来减少胆固醇的生物合成,从而有效地降低机体总胆固醇和低密度脂蛋白胆固醇水平。除此以外,他汀类药物还存在改善内皮功能、减少斑块部位的炎症及氧化应激、稳定斑块及减少血栓形成等多种作用。最近研究显示,他汀影响膜蛋白ABCA1表达水平及其介导的巨噬细胞胆固醇外流过程。巨噬细胞胆固醇外流是胆固醇逆向转运过程中的关键限速步骤。机体通过胆固醇逆向转运将动脉壁过多的胆固醇运送回到肝脏,促进其经胆道排泄,从而拮抗动脉粥样硬化发生。ABCG1介导的胆固醇外流与ABCA1途径同为巨噬细胞胆固醇外流的两大重要途径。目前对于他汀类药物是否影响ABCG1介导的巨噬细胞胆固醇外流过程尚无报道。本研究拟通过评价他汀类药物对膜蛋白ABCG1表达及功能的影响,来全面了解他汀对巨噬细胞胆固醇外流过程的影响,并探讨其可能的作用机制。
研究目的
1.评价他汀类药物对巨噬细胞中ABCG1mRNA及蛋白表达水平的影响；
2.评价他汀类药物对ABCG1介导的巨噬细胞胆固醇外流功能的影响,并探讨可能的作用机制；
方法
1.分别使用不同浓度阿托伐他汀和辛伐他汀孵育体外培养的THP-1和PBMCs巨噬细胞。通过测定胆固醇外流率,评价他汀类药物对巨噬细胞胆固醇外流功能的影响；
2.通过荧光实时定量PCR以及免疫印迹Western blotting方法分别检测他汀作用前后细胞中ABCG1和ABCA1mRNA及蛋白表达水平的变化；
3.使用荧光实时定量PCR检测巨噬细胞中ABCG1两种亚型ABCG1-S和ABCG1-L在他汀作用前后mRNA水平变化；分别测定胆固醇外流率来评价ABCG1-S与ABCG1-L之间的功能差异；
4.通过生物素标记巨噬细胞膜表面蛋白,结合亲和素免疫共沉淀方法,分析他汀作用下巨噬细胞膜表面ABCG1蛋白表达变化；
5.使用LXR激动剂TO-901317联合他汀孵育THP-1巨噬细胞,测定药物作用前后巨噬细胞胆固醇外流率变化,并检测ABCG1两种亚型mRNA水平变化。比较联合使用LXR激动剂与单用他汀时,ABCG1基因表达和功能的改变。探讨相关作用机制。
结果
1.辛伐他汀孵育THP-1巨噬细胞24小时后,ABCG1介导的巨噬细胞胆固醇外流率显著降低,对照组外流率17.3%±0.8%,1μM辛伐他汀组降至13.5%±1.2%(n=4,p<0.01)。当使用10μM辛伐他汀孵育细胞,胆固醇外流率进一步下降至11.5%±0.6%(n=4,p<0.01)；使用阿托伐他汀孵育THP-1细胞24小时,ABCG1介导的胆固醇外流率亦呈显著降低,对照组外流率17.3%±0.8%,1μM阿托伐他汀组外流率降至14.4%±1.1%(n=4,p<0.01),10μM阿托伐他汀组外流率11.6%±1.4%(n=4,p<0.01);PBMCs巨噬细胞中实验结果与THP-1结果相似；
2.阿托伐他汀孵育细胞24小时,THP-1或PBMCs巨噬细胞内ABCG1蛋白表达未见明显改变；换用辛伐他汀孵育细胞,所观察到的结果与之类似；与ABCG1表达结果相对,他汀孵育24小时后THP-1或PBMCs巨噬细胞中ABCA1蛋白水平呈现明显降低,显示他汀对两种膜转运蛋白表达可能存在不同作用；
3.阿托伐他汀10μM或辛伐他汀10μM孵育细胞24小时,THP-1巨噬细胞膜表面的ABCG1表达水平未见明显改变,说明他汀并没有影响ABCG1在巨噬细胞膜表面的表达；
4.他汀孵育THP-1细胞24小时后,使用荧光实时定量PCR检测细胞中ABCG1两种亚型-ABCG1-S和ABCG1-L mRNA表达水平,结果显示1μM辛伐他汀组ABCG1-S/ABCG1-L mRNA比值从孵育前1.4±0.17降为0.7±0.13(n=4,p<0.01),10μM辛伐他汀组降为0.14±0.03(n=4,p<0.01)；而10μM阿托伐他汀孵育24小时后ABCG1-S/ABCG1-L mRNA比值降为0.24±0.05(n=4,p<0.01)。表明他汀类药物显著影响ABCG1两种亚型的表达水平；
5.他汀联合TO-901317组与单用他汀组相比,ABCG1-S/ABCG1-L mRNA表达比值显著增加；提示小剂量TO-901317(lnM)能够拮抗他汀所导致ABCG1亚型表达变化；
6.巨噬细胞胆固醇外流率测定结果显示,单用10μM辛伐他汀组胆固醇外流率为12.4%±1.2%,联用1nM TO-901317后胆固醇外流率增至16%±2.5%；单用10μM阿托伐他汀组胆固醇外流率为11.3%±0.5%,联用1nM TO-901317后胆固醇外流率增至15.2%±1.5%(n=4p<0.05)；提示小剂量TO-901317能够改善他汀引起的ABCG1胆固醇外流率降低。
结论
1.阿托伐他汀和辛伐他汀降低ABCG1介导的巨噬细胞胆固醇外流功能。其作用可能通过LXR依赖性方式进行；
2.他汀作用不改变ABCG1,总蛋白表达水平,但是改变了具有功能差异的两种ABCG1蛋白亚型在巨噬细胞中的表达比例,从而影响ABCG1总体功能,这可能代表了ABCG1基因一种新的功能调节方式；
3.他汀与LXR激动剂联合使用可能能够减少他汀类药物影响巨噬细胞胆固醇外流的副作用,从而增加临床获益。
Part Ⅰ
Background:
Macrophage cholesterol efflux is the initial step of reverse cholesterol transport, and provides protection against atherosclerosis. Lipid transporters ABCA1and ABCG1are essential components of macrophage cholesterol efflux, and play important but different roles in this process. Both in vitro and in vivo studies show that ABCA1functions in transporting cellular cholesterol from macrophage to lipid-poor apoA-1lipoprotein, whereas ABCG1transports cholesterol to mature HDL. Although studies have demonstrated anti-atherosclerosis effect of ABCA1, functional role of ABCG1in atherosclerosis remains controversial, mostly because of inconsistent results from animal studies. Recently, our lab performed an association study on ABCG1gene polymorphisms with coronary artery disease in humans. We found that human ABCG1-367G>A polymorphism located in the gene promote region was significantly associated with decreased risk for coronary artery disease and myocardial infarction. For the first time, our findings showed that ABCG1gene may promote development of atherosclerosis in humans. In this project, we further investigate whether the ABCG1genetic variant may alter the gene function, and explore the underlying mechanisms.
Objective:
1. To determine if ABCG1-367G>A polymorphism have an influence on the gene expression.
2. To evaluate if ABCG1-367G>A polymorphism have an influence on function of ABCG1-mediated cholesterol efflux.
3. To determine if ABCG1-367G>A polymorphism impair transcription factor binding and promoter activity.
Methods and Results:
1. Peripheral blood mononuclear cells were isolated from healthy subjects through Ficoll-Paque density gradient centrifugation and differentiated into macrophages using human macrophage colony-stimulating factor. We measured ABCG1mRNA level in macrophages from human subjects with different genotypes for ABCG1-367G>A using quantitative real-time PCR. Our results showed that ABCG1mRNA expression was significantly lower in macrophages from subjects with AA genotype than that in subjects with GG genotype (0.41±0.10of A/A, n=5; vs. G/G, n=25; p<0.01). ABCG1mRNA expression was also decreased in subjects with G/A genotype (0.87±0.04, n=22, p<0.01).
2. Through Western blot analysis, ABCG1protein level appeared significantly lower in macrophages from A/A subjects compared to that of G/G subjects (p<0.01). G/A subjects also showed a significantly lower ABCG1protein level compared to G/G subjects (p<0.05). On the other hand, ABCA1and SR-B1protein levels showed no significant difference between G/G, G/A and A/A subject groups.
3. We evaluate effect of ABCG1-367G>A polymorphism on the gene function by measuring ABCG1-mediated cholesterol efflux. The results showed that percentage cholesterol efflux of macrophages from A/A subjects (22.9%±3.8%, n=4) was lower than that of macrophages from either G/G (29.6%±2.1%, n=15, p<0.01) or G/A subjects (24.9%±2.9%, n=10,p<0.01). There was no significant difference between G/G and G/A subjects (p>0.05).
4. To examine whether the ABCG1-367G>A affect promoter transcriptional activity, we measured luciferase activity of ABCG1promoter construct containing the substitution. Our results showed that relative luciferase activity of p-A construct was significantly lower than that of wild-type p-G construct in HEK293T cells under either basal or TO-901317activated conditions. The results were confirmed in another two different cell lines, HepG2and THP-1cells.
5. We performed electrophoretic mobility shift assay and evaluated whether ABCG1-367G>A polymorphism may affect specific transcription factor binding. The results showed that one major DNA-protein complex was detected using the probe corresponding to the G allele, and its band intensity was markedly reduced in the presence of unlabelled G allele. There was no major band detected in the assay using the A allele probe.
6. We examined mRNA expressions of proapoptotic genes using quantitative real-time PCR. The results showed that bok mRNA level was significantly increased in macrophages from A/A and G/A subjects compared to that of G/G subjects. The bid mRNA level was also increased in A/A and G/A macrophages compared to that of G/G macrophages.
Conclusion:
The ABCG1-367G>A variant impaired transcription factor binding of the promoter and decreased its transcriptional activity. The genetic variant has an allele-specific effect on ABCG1gene expression and function in human macrophages, which provide evidence of a genotypic effect on atherosclerosis.
Part II
Background:
Statins are competitive inhibitors for3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-controlling enzyme in cholesterol synthesis. They are the most widely used cholesterol-lowering agents for lowering low-density lipoprotein (LDL) cholesterol concentration and for prevention of coronary artery disease. They reduce LDL-cholesterol concentration through the blockade of mevalonate pathway, the metabolic pathway that produces cholesterol, and the increases of LDL catabolism. Besides the effects on lowering LDL-cholesterol, statins showed pleiotropic effects including improving endothelial function, enhancing the stability of atherosclerotic plaques, decreasing oxidative stress and inflammation, and inhibiting the thrombogenic response. In addition, recent studies show that statins treatment may have influence on macrophage cholesterol efflux. Statins reduce ABCA1expression and ABCA1-mediated cholesterol efflux in macrophages. While statins effect on ABCG1, another important lipid transporter for macrophage cholesterol efflux, is still unclear. Here, we investigated statins effect on expression and functionality of ABCG1in human macrophages, and explore the underlying mechanism.
Objective:
1. To determine statins effect on ABCG1expression level in human macrophages.
2. To examine statins effect on ABCG1function, and explore the underlying mechanism.
Methods and Results:
Statins treatment significantly decreased ABCG1-mediated cholesterol efflux in human macrophages (From33.8%±2.8%of control to22.9%±1.7%of10μM simvastatin; or to23.3%±3.3%of10μM atorvastatin,p<0.01, n=4), whereas the protein expression of ABCG1remained unaltered on statins. The cell surface expression of ABCG1was also unaltered on statins. Further analysis revealed that two major ABCG1isoforms responded to statins differently. The expression of ABCG1-S,which exhibited higher activity in cholesterol efflux than that of ABCG1-L, was significantly decreased on statins compared to increased expression of ABCG1-L. The mRNA ratio of ABCG1-S/ABCG1-L was significantly decreased in THP-1cells under either1μM simvastatin (1.4±0.17of control to0.69±0.06of1μM simvastatin, n=4,p<0.01), or1μM atorvastatin (0.7±0.13,/p<0.01). Further changes on ABCG1-S/ABCG1-L ratio were observed under either10μM simvastatin (0.14±0.03, n=4, p<0.01), or10μM atorvastatin (0.24±0.05, n=4, p<0.01). Similar results were observed in PBMCs. The results suggested that the proportion change of ABCG1isoforms expressions could contribute to reduced ABCG1functionality under statins treatment. The statins effects on ABCG1isoforms expression and functionality was reversed by low-dose LXR agonist, TO-901317, indicating that statins down-regulation of ABCG1functionality was likely through LXR dependent pathway.
Conclusion:
In conclusion, simvastain and atorvastain decreased ABCG1-mediated cholesterol efflux in human macrophages without alteration of total ABCG1protein level. The proportion change of ABCG1isoforms expressions may be involved in the down-regulation of ABCG1functionality by statins, which provided a novel mechanism for the regulation of ABCG1function.
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