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1.
油酸对THP-1巨噬细胞源性泡沫细胞三磷酸腺苷结合盒转运体A1表达和胆固醇流出的影响 总被引：21，自引：0，他引：21
以THP 1巨噬细胞源性泡沫细胞为研究对象 ,观察油酸对THP 1巨噬细胞源性泡沫细胞胆固醇流出和三磷酸腺苷结合盒转运体A1(ABCA1)表达的影响 ,以探讨油酸对动脉粥样硬化发生发展的影响。用液体闪烁计数器检测细胞内胆固醇流出 ,高效液相色谱分析细胞内总胆固醇、游离胆固醇和胆固醇酯含量 ,运用逆转录多聚酶链反应和Western印迹分别检测ABCA1mRNA与ABCA1蛋白的表达 ,采用流式细胞术检测细胞平均ABCA1荧光强度。实验显示油酸引起THP 1巨噬细胞源性泡沫细胞总胆固醇、游离胆固醇与胆固醇酯呈时间依赖性增加 ,而ABCA1蛋白水平、细胞平均ABCA1荧光强度以及apoA I介导的胆固醇流出呈时间依赖性减少 ,细胞内胆固醇增多 ,但ABCA1mRNA没有明显变化。结果表明 ,油酸减少THP 1巨噬细胞源性泡沫细胞ABCA1蛋白水平 ,降低细胞内胆固醇流出 ,增加细胞内胆固醇聚积。 相似文献
2.
正三磷酸腺苷结合盒转运体A1(ATP-binding cassette transporter A1,ABCA1)作为介导细胞内脂质流出,维持细胞脂质代谢平衡的重要跨膜蛋白,对动脉粥样硬化(atherosclerosis,AS)的防治具有重要意义[1].近日,清华大学结构生物学高精尖创新中心的颜宁教授与龚欣博士组成的研究团队(Cell,2017,169:1228-1239)采用冷冻电子显微镜技术,经过重组人全长ABCA1蛋白制备、透射电子显微 相似文献
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动脉粥样硬化小型猪三磷酸腺苷结合盒转运体Al表达的变化 总被引：2，自引：0，他引：2
用贵州小香猪建立动脉粥样硬化动物模型,探讨动脉粥样硬化小型猪三磷酸腺苷结合盒转运体Al(ABCAl)表达的变化．采用血管内膜损伤法加高脂高胆固醇饲料喂养贵州小香猪,建立动脉粥样硬化动物模型．血浆总胆固醇、甘油三酯和高密度脂蛋白胆固醇的浓度均用氧化酶法测定,采用逆转录聚合酶链反应检测ABCAlmRNA水平,蛋白质印迹和免疫组织化学检测ABCAl蛋白质的表达．喂养12个月后,实验组与正常对照组比较,空腹血浆总胆固醇、甘油三酯和高密度脂蛋白胆固醇水平升高;实验组小型猪主动脉、髂动脉、颈总动脉和冠状动脉可见动脉粥样硬化斑块和脂质条纹;实验组小型猪肝组织、主动脉、小肠组织ABCAl表达上调．结果提示,采用血管内膜损伤法加高脂高胆固醇饲料喂养小型猪可建立动脉粥样硬化动物模型．动脉粥样硬化小型猪肝组织、主动脉和小肠组织ABCAl表达上调． 相似文献
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三磷酸腺苷结合盒转运体A1(ABCA1)、三磷酸腺苷结合盒转运体G1(ABCG1)和B族Ⅰ型清道夫受体(SR-BⅠ)介导的胆固醇外流是巨噬细胞内3条主要的胆固醇外流途径,对维持细胞内胆固醇动态平衡至关重要,其中转运体的功能及其表达的调节、胞外接受体的数量和活性等对细胞内胆固醇外流效率有重要的决定作用．最新研究发现,动脉粥样硬化(As)病变中出现的脂类蓄积、炎症、氧化应激、缺氧和胰岛素抵抗等病理情况,显著影响胆固醇转运体的表达,进而影响胆固醇外流及As的发生发展．本文主要针对As病变细胞内各胆固醇外流途径的作用及常伴随的脂类蓄积、炎症、氧化应激、缺氧和胰岛素抵抗现象,对胆固醇转运体表达调节的最新进展做一综述,以期为As治疗提供新理论依据和药物靶点,推动As治疗方法的发展． 相似文献
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作为一种有效的降脂药物,普罗布考能够降低血浆高密度脂蛋白胆固醇(HDL-C)水平并抑制动脉粥样硬化,但其机制尚未完全阐明．本研究的目的旨在进一步阐明普罗布考降脂及抗动脉粥样硬化的机理．将新西兰白兔随机分为4组：正常饮食组、正常饮食+普罗布考组、高脂饮食组(HFD组)、高脂饮食+普罗布考组(HFD+P组)．结果显示,处理7周后,与HFD组比较,HFD+P组动脉粥样硬化病变程度、肝脏脂质蓄积明显减轻,血浆甘油三脂、总胆固醇、低密度脂蛋白胆固醇及HDL-C 水平降低,肝脏中清道夫受体-BⅠ(SR-BⅠ)以及肝脏与小肠中三磷酸腺苷结合盒转运体(ABC)G5(ABCG5)、ABCG8表达上调,肝脏中ABCA1表达下调,主动脉弓与血浆肿瘤坏死因子α、白介素1、白介素6、单核趋化蛋白1水平降低．这些结果表明普罗布考的抗动脉粥样硬化作用可能与其调控ABCA1、SR-BⅠ、ABCG5、ABCG8表达及抑制促炎介质的分泌有关． 相似文献
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三磷酸腺苷结合盒转运体A1(ABCA1)是体内胆固醇逆向转运的关键环节.对氧磷是广泛使用的有机磷农药的活性代谢产物.研究发现,对氧磷能增加巨噬细胞中胆固醇的堆积,但具体机制还不清楚.以RAW264.7巨噬细胞源性泡沫细胞为研究对象,观察对氧磷对RAW264.7巨噬细胞源性泡沫细胞ABCA1表达和胆固醇流出的影响并探讨其机制.结果显示,对氧磷以时间和剂量依赖的方式增加RAW264.7巨噬细胞源性泡沫细胞中总胆固醇、游离胆固醇和胆固醇酯水平,降低ABCA1表达和胆固醇流出,同时对氧磷降低细胞中环磷酸腺苷(cAMP)的水平及腺苷酸环化酶(AC)的活性和增加磷酸二酯酶(PDE)的活性,而cAMP的类似物双丁酰环腺苷酸(dBcAMP)能够阻断对氧磷降低ABCA1表达和部分阻断对氧磷降低胆固醇流出,对氧磷导致的cAMP水平的降低也可被AC激动剂福斯高林(Forskolin)和PDE抑制剂3-异丁基-1-甲基黄嘌呤(IBMX)所阻断.以上结果表明,对氧磷通过cAMP信号通路下调RAW264.7巨噬细胞源性泡沫细胞ABCA1的表达,降低细胞内胆固醇流出和增加细胞内胆固醇堆积. 相似文献
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以THP-1巨噬细胞源性泡沫细胞为研究对象,观察干扰素-γ(IFN-γ)对THP-1巨噬细胞源性泡沫细胞胆固醇流出和三磷酸腺苷结合盒转运体A1(ABCA1)表达的影响.以便探讨IFN-γ在动脉粥样硬化发生发展中的作用.采用液体闪烁计数器检测细胞内胆固醇流出, 高效液相色谱分析细胞内总胆固醇、游离胆固醇和胆固醇酯含量.运用逆转录-多聚酶链反应和蛋白质印迹分别检测ABCA1 mRNA与ABCA1蛋白质的表达, 采用流式细胞术检测细胞平均ABCA1荧光强度.发现IFN-γ引起THP-1巨噬细胞源性泡沫细胞总胆固醇、游离胆固醇与胆固醇酯呈时间依赖性增加, 而ABCA1 mRNA和蛋白质表达、细胞平均ABCA1荧光强度以及apoA-1介导的胆固醇流出呈时间依赖性减少, 细胞内胆固醇增多.结果表明IFN-γ抑制THP-1巨噬细胞源性泡沫细胞ABCA1表达及细胞内胆固醇流出,同时增加细胞内胆固醇聚积. 相似文献
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用贵州小香猪建立动脉粥样硬化动物模型,探讨动脉粥样硬化小型猪三磷酸腺苷结合盒转运体 A1(ABCA1) 表达的变化 . 采用血管内膜损伤法加高脂高胆固醇饲料喂养贵州小香猪,建立动脉粥样硬化动物模型 . 血浆总胆固醇、甘油三酯和高密度脂蛋白胆固醇的浓度均用氧化酶法测定,采用逆转录聚合酶链反应检测 ABCA1mRNA 水平,蛋白质印迹和免疫组织化学检测 ABCA1 蛋白质的表达 . 喂养 12 个月后,实验组与正常对照组比较,空腹血浆总胆固醇、甘油三酯和高密度脂蛋白胆固醇水平升高;实验组小型猪主动脉、髂动脉、颈总动脉和冠状动脉可见动脉粥样硬化斑块和脂质条纹;实验组小型猪肝组织、主动脉、小肠组织 ABCA1 表达上调 . 结果提示,采用血管内膜损伤法加高脂高胆固醇饲料喂养小型猪可建立动脉粥样硬化动物模型 . 动脉粥样硬化小型猪肝组织、主动脉和小肠组织 ABCA1 表达上调 . 相似文献
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Phospholipid transfer protein (PLTP) facilitates the transfer of phospholipids from triglyceride-rich lipoproteins into HDL. PLTP has been shown to be an important factor in lipoprotein metabolism and atherogenesis. Here, we report that chronic high-fat, high-cholesterol diet feeding markedly increased plasma cholesterol levels in C57BL/6 mice. PLTP deficiency attenuated diet-induced hypercholesterolemia by dramatically reducing apolipoprotein E-rich lipoproteins (-88%) and, to a lesser extent, LDL (-40%) and HDL (-35%). Increased biliary cholesterol secretion, indicated by increased hepatic ABCG5/ABCG8 gene expression, and decreased intestinal cholesterol absorption may contribute to the lower plasma cholesterol in PLTP-deficient mice. The expression of proinflammatory genes (intercellular adhesion molecule-1 and vascular cell adhesion molecule-1) is reduced in aorta of PLTP knockout mice compared with wild-type mice fed either a chow or a high-cholesterol diet. Furthermore, plasma interleukin-6 levels are significantly lower in PLTP-deficient mice, indicating reduced systemic inflammation. These data suggest that PLTP appears to play a proatherogenic role in diet-induced hyperlipidemic mice. 相似文献
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Abe-Dohmae S Kato KH Kumon Y Hu W Ishigami H Iwamoto N Okazaki M Wu CA Tsujita M Ueda K Yokoyama S 《Journal of lipid research》2006,47(7):1542-1550
Serum amyloid A (SAA) is an amphiphilic helical protein that is found associated with plasma HDL in various pathological conditions, such as acute or chronic inflammation. Cellular lipid release and generation of HDL by this protein were investigated, in comparison with the reactions by apolipoprotein A-I (apoA-I) and several types of cells that appear with various specific profiles of cholesterol and phospholipid release. SAA mediated cellular lipid release from these cells with the same profile as apoA-I. Upregulation of cellular ABCA1 protein by liver X receptor/retinoid X receptor agonists resulted in an increase of cellular lipid release by apoA-I and SAA. SAA reacted with the HEK293-derived clones that stably express human ABCA1 (293/2c) or ABCA7 (293/6c) to generate cholesterol-containing HDL in a similar manner to apoA-I. Dibutyryl cyclic AMP and phorbol 12-myristate 13-acetate, which differentiate apoA-I-mediated cellular lipid release between 293/2c and 293/6c, also exhibited the same differential effects on the SAA-mediated reactions. No evidence was found for the ABCA1/ABCA7-independent lipid release by SAA. Characterization of physicochemical properties of the HDL revealed that SAA-generated HDL particles had higher density, larger diameter, and slower electrophoretic mobility than those generated by apoA-I. These results demonstrate that SAA generates cholesterol-containing HDL directly with cellular lipid and that the reaction is mediated by ABCA1 and ABCA7. 相似文献
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The assembly of HDL by helical apolipoprotein and cellular lipid was studied using HEK293 cells to which ecdysone-inducible human ABCA1 or human ABCA7 was transfected. Expression of both ABCA1 and ABCA7 was induced linearly proportional to ponasterone A concentration in the medium. In the experimental conditions used, the ABC protein expression levels limited the rate of lipid release when the apolipoprotein concentration was high, and the apolipoprotein concentration was rate-limiting when the ABC protein expression levels were high. When ABCA1 expression increased in conditions in which it was rate-limiting, relative cholesterol content to phospholipid increased in the HDL produced. In contrast, it was constant when ABCA7 expression increased. To investigate the background mechanism, the HDL particles were analyzed by density gradient ultracentrifugation and high performance lipid chromatography. The ABCA1-mediated reaction produced two distinct HDLs, large cholesterol-rich and small cholesterol-poor particles, and the ABCA7-mediated reaction generated mostly small cholesterol-poor particles. The increase of HDL assembly with the increase of ABCA1 expression was predominant in large cholesterol-rich particles, whereas only small cholesterol-poor HDL increased as ABCA7 expression increased. We conclude that ABCA1 generates cholesterol-rich and cholesterol-poor HDL and that the former is more prominently dependent on the increase of ABCA1 expression. ABCA7 produces this HDL subfraction only as a very minor component. 相似文献
14.
Langheim S Yu L von Bergmann K Lütjohann D Xu F Hobbs HH Cohen JC 《Journal of lipid research》2005,46(8):1732-1738
The major pathway for the removal of cholesterol from the body is via secretion into the bile. Three members of the ATP binding cassette (ABC) family, ABCG5 (G5), ABCG8 (G8), and ABCB4 (MDR2), are required for the efficient biliary export of sterols. Here, we examined the interdependence of these three ABC transporters for biliary sterol secretion. Biliary lipid levels in mice expressing no MDR2 (Mdr2-/- mice) were compared with those of Mdr2-/- mice expressing 14 copies of a human G5 (hG5) and hG8 transgene (Mdr2-/-;hG5G8Tg mice). Mdr2-/- mice had only trace amounts of biliary cholesterol and phospholipids. The Mdr2-/-;hG5G8Tg mice had biliary cholesterol levels as low as those of Mdr2-/- mice. Thus, MDR2 expression is required for G5G8-mediated biliary sterol secretion. To determine whether the reduction in fractional absorption of dietary sterols associated with G5G8 overexpression is secondary to the associated increase in biliary cholesterol, we compared the fractional absorption of sterols in Mdr2-/-;hG5G8Tg and hG5G8Tg animals. Inactivation of MDR2 markedly attenuated the reduction in fractional sterol absorption associated with G5G8 overexpression. These results are consistent with the notion that increased biliary cholesterol secretion contributes to the reduction in fractional sterol absorption associated with G5G8 overexpression. 相似文献
15.
The ATP binding cassette transporters ABCG5 (G5) and ABCG8 (G8) limit the accumulation of neutral sterols by restricting sterol uptake from the intestine and promoting sterol excretion into bile. Humans and mice lacking G5 and G8 (G5G8-/-) accumulate plant sterols in the blood and tissues. However, despite impaired biliary cholesterol secretion, plasma and liver cholesterol levels are lower in G5G8-/- mice than in wild-type littermates. To determine whether the observed changes in hepatic sterol metabolism were a direct result of decreased biliary sterol secretion or a metabolic consequence of the accumulation of dietary noncholesterol sterols, we treated G5G8-/- mice with ezetimibe, a drug that reduces the absorption of both plant- and animal-derived sterols. Ezetimibe feeding for 1 month sharply decreased sterol absorption and plasma levels of sitosterol and campesterol but increased cholesterol in both the plasma (from 60.4 to 75.2 mg/dl) and the liver (from 1.1 to 1.87 mg/g) of the ezetimibe-treated G5G8-/- mice. Paradoxically, the increase in hepatic cholesterol was associated with an increase in mRNA levels of HMG-CoA reductase and synthase. Together, these results indicate that pharmacological blockade of sterol absorption can ameliorate the deleterious metabolic effects of plant sterols even in the absence of G5 and G8. 相似文献
16.
Noboru Ōtake Katsumi Kakinuma Hiroshi Yonehara 《Bioscience, biotechnology, and biochemistry》2013,77(12):2777-2780
Separation of the active principles of DX.C was worked out into eight groups with the use of an ion exchange chromatography. Further purification of main components, the isolation and characterization of two main active principles were described. 相似文献
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Recent developments in lipid metabolism have shown the importance of ATP binding cassette transporters (ABCs) in controlling cellular and total body lipid homeostasis. ABCA1 mediates the transport of cholesterol and phospholipids from cells to lipid-poor apolipoprotein A-I (apoA-I), whereas ABCG1 and ABCG4 mediate the transport of cholesterol from cells to lipidated lipoproteins. ABCA1, ABCG1, and ABCG4 are all expressed in cholesterol-loaded macrophages, and macrophages from ABCA1 and ABCG1 knockout mice accumulate cholesteryl esters. Here, we show that the lipidated particles generated by incubating cells overexpressing ABCA1 with apoA-I are efficient acceptors for cholesterol released from cells overexpressing either ABCG1 or ABCG4. The cholesterol released to the particles was derived from a cholesterol oxidase-accessible plasma membrane pool in both ABCG1 and ABCG4 cells, which is the same pool of cholesterol shown previously to be removed by high density lipoproteins. ABCA1 cells incubated with apoA-I generated two major populations of cholesterol- and phospholipid-rich lipoprotein particles that were converted by ABCG1 or ABCG4 cells to one major particle population that was highly enriched in cholesterol. These results suggest that ABCG1 and ABCG4 act in concert with ABCA1 to maximize the removal of excess cholesterol from cells and to generate cholesterol-rich lipoprotein particles. 相似文献
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The oxysterol-activated nuclear receptor liver X receptor alpha (LXRalpha) has been implicated in the control of both cholesterol and fatty acid metabolism. In this study, we have evaluated the effects of excess dietary cholesterol on hepatic cholesterol metabolism, lipogenesis, and VLDL production in homozygous (Lxralpha(-/-)), heterozygous (Lxralpha(+/-)), and wild-type mice. Mice were fed either chow or a cholesterol-enriched diet (1%, w/w) for 2 weeks. On the high-cholesterol diet, fractional cholesterol absorption was higher in Lxralpha(-/-) mice than in controls, leading to delivery of more dietary cholesterol to the liver. Lxralpha(-/-) mice were not able to induce expression of hepatic Abcg5/Abcg8, and massive accumulation of free cholesterol and cholesteryl esters (CEs) occurred. Interestingly, despite the inability to upregulate Abcg5/Abcg8, the highly increased hepatic free cholesterol content did stimulate biliary cholesterol output in Lxralpha(-/-) mice. Hepatic cholesterol accumulation was accompanied by decreased hepatic expression of lipogenic genes, probably caused by impaired sterol-regulatory element binding protein 1c processing, lower hepatic triglyceride (TG) contents, strongly reduced plasma TG concentrations (-90%), and reduced VLDL-TG production rates (-60%) in Lxralpha(-/-) mice. VLDL particles were smaller and CE-enriched under these conditions. Lxralpha deficiency did not affect VLDL formation under chow-fed conditions. Hepatic stearyl coenzyme A desaturase 1 expression was decreased dramatically in Lxralpha(-/-) mice and did not respond to cholesterol feeding, but fatty acid profiles of liver and VLDL were only slightly different between Lxralpha(-/-) and wild-type mice. Our data indicate that displacement of TGs by CEs during the VLDL assembly process underlies hypotriglyceridemia in cholesterol-fed Lxralpha(-/-) mice. 相似文献
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Plant stanols and sterols of the 4-desmethyl family (e.g., sitostanol and sitosterol) effectively decrease LDL cholesterol concentrations, whereas 4,4-dimethylsterols (alpha-amyrin and lupeol) do not. Serum carotenoid concentrations, however, are decreased by both plant sterol families. The exact mechanisms underlying these effects are not known, although effects on micellar composition have been suggested. With a liver X receptor (LXR) coactivator peptide recruitment assay, we showed that plant sterols and stanols from the 4-desmethylsterol family activated both LXRalpha and LXRbeta, whereas 4,4-dimethyl plant sterols did not. In fully differentiated Caco-2 cells, the functionality of this effect was shown by the increased expression of ABCA1, one of the known LXR target genes expressed by Caco-2 cells in measurable amounts. The LXR-activating potential of the various plant sterols/stanols correlated positively with ABCA1 mRNA expression. Reductions in serum hydrocarbon carotenoids could be explained by the effects of the 4-desmethyl family and 4,4-dimethylsterols on micellar carotenoid incorporation. Our findings indicate that the decreased intestinal absorption of cholesterol and carotenoids by plant sterols and stanols is caused by two distinct mechanisms. 相似文献
20.
ATP binding cassette transporter A1 - key roles in cellular lipid transport and atherosclerosis 总被引：8，自引：0，他引：8
Srivastava N 《Molecular and cellular biochemistry》2002,237(1-2):155-164
ATP-binding cassette transporter A1 (ABCA1) was recently recognized as the mutant molecule responsible for Tangier disease with low HDL levels, accumulation of cholesteryl esters in tissues, and increased risk of cardiovascular disease. Extensive studies for the past 2 years have recognized the critical role of ABCA1 in cholesterol and phospholipid trafficking. Since the removal of cholesterol from tissues is a key step in the prevention of atherosclerosis, significant attention has been focused on this molecule. Natural ABCA1 mutations in Tangier disease (TD) patients and WHAM chickens together with induced mutation in ABCA1 knock-out mice unequivocally established the important role of ABCA1 in maintaining circulating HDL levels and promoting cholesterol efflux from the arterial wall. Mice lacking ABCA1 showed similar phenotypes observed in Tangier disease patients with low levels of HDL. Further understanding of the roles of ABCA1 in lipid transport and atherosclerosis became clear from studies with ABCA1 transgenic mice. These mice showed enhanced cholesterol efflux from macrophages and reduced atherosclerotic lesion formation. The promoter of the ABCA1 gene has been mapped to a large extent, with the exception of cAMP response element. The present review summarizes recent developments on the role of ABCA1 in cholesterol efflux and prevention of atherosclerosis. Given the antiatherogenic properties of ABCA1, this molecule can serve as an appropriate target for developing drugs to treat individuals with low levels of HDL. 相似文献