ATP-binding cassette transporter A1 (ABCA1) is critical in exporting cholesterol from macrophages and plays a protective role in the development of atherosclerosis. The purpose of this study was to investigate the effects of betulinic acid (BA), a pentacyclic triterpenoid, on ABCA1 expression and cholesterol efflux, and to further determine the underlying mechanism. BA promoted ABCA1 expression and cholesterol efflux, decreased cellular cholesterol and cholesterol ester content in LPS-treated macrophages. Furthermore, we found that BA promoted ABCA1 expression via down-regulation of miR-33s. The inhibition of LPS-induced NF-κB activation further decreased miR-33s expression and enhanced ABCA1 expression and cholesterol efflux when compared with BA only treatment. In addition, BA suppressed IκB phosphorylation, p65 phosphorylation and nuclear translocation, and the transcription of NF-κB-dependent related gene. Moreover, BA reduced atherosclerotic lesion size, miR-33s levels and NF-κB activation, and promoted ABCA1 expression in apoE(-/-) mice. Taken together, these results reveal a novel mechanism for the BA-mediated ABCA1 expression, which may provide new insights for developing strategies for modulating vascular inflammation and atherosclerosis.

BACKGROUND:Tert-butylhydroquinone (tBHQ), a synthetic phenolic antioxidant, is commonly used as a food preservative because of its potent antilipid peroxidation activity. Several lines of evidence have demonstrated that dietary supplementation with antioxidants has an antiatherogenic function through reducing cholesterol uptake or promoting reverse cholesterol transport. In this study, we investigated whether tBHQ affects expression of ATP-binding cassette transporter A1 (ABCA1) and the potential subsequent effect on cellular cholesterol homeostasis.METHODS AND RESULTS:tBHQ increased ABCA1 protein levels and markedly enhanced cholesterol efflux from THP-1 macrophage-derived foam cells. Furthermore, tBHQ reduced calpain-mediated ABCA1 proteolysis via activation of nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). Inhibition of HO-1 with a pharmacological inhibitor or siRNA and knockdown of Nrf2 suppressed the stimulatory effects of tBHQ on ABCA1 expression and calpain activity.CONCLUSIONS:Nrf2/HO-1 signaling is required for the regulation by tBHQ of ABCA1 expression and cholesterol efflux in macrophage-derived foam cells and an antiatherogenic role of tBHQ is suggested.

ATP-binding cassette transporter 1(ABCA1) mediated lipid efflux and evolved to maintain cholesterol homeostasis.Newborn ABCA1 should through intracellular transport and chemical modification,ultimately being a mature functional transporter with its function of lipid transport.The intracellular transport and correct localization of ABCA1 plays an important role in its function.ABCA1 researches focused on the lipid transport,and proposed the model of the various cholesterol efflux mechanisms,such as channel transport model,mushroom-like protuberances model and retroendocytosis model.Recent studies have shown,ABCA1 can regulate the plasma membrane lipid rafts,and involve in immune and inflammatory regulation.This review focuses on the current views on intracellular transport and various functions of ABCA1,in order to provide the new therapeutic targets for atherosclerosis-related diseases.

Apelin has an antiatherogenic function through activating protein kinase C (PKC) to initiate a series of cellular signaling pathways. PKC phosphorylates and stabilizes ATP-binding cassette transporter A1 (ABCA1) through inhibiting its degradation mediated by calpain. Thus, in the present study, we investigated whether apelin-13 affects expression of ABCA1 through PKC signaling. The results showed that apelin-13 dramatically increased cholesterol efflux from THP-1 macrophage-derived foam cells and reduced cellular cholesterol levels. ABCA1 protein but not mRNA levels were dramatically increased by apelin-13, and calpain-induced degradation of ABCA1 and calpain activity were suppressed with treatment of apelin-13. However, the effects of apelin-13 on ABCA1 protein expression, cellular cholesterol efflux and calpain activity were abolished by depletion of PKCα, suggesting the potential important role of PKCα. In addition, apelin-13 was shown to phosphorylate serine residues in ABCA1 through the PKCα pathway. Thus, apelin-13 appears to activate PKCα, phosphorylate ABCA1 and inhibit calpain-mediated proteolysis, thereby promoting cholesterol efflux and reducing foam cell formation. Our study herein described a possible mechanism for understanding the antiatherogenic effects of apelin on attenuating the progression of atherosclerosis.

<正>目的:观察LPS促巨噬细胞脂质蓄积时SREBP-2及miR-33a的表达情况,并探讨miR-33a在其中的作用。方法:采用THP-1巨噬细胞构建泡沫细胞模型,使用LPS刺激巨噬细胞,用PDTC特异性地阻断LPS的炎症作用,RT-PCR检测细胞

The major pathways of cholesterol efflux from macrophages are the transmembrane transports mediated by membrane proteins involved ATP-binding cassette transporters A1, ATP-binding cassette transporters G1 and scavenger receptor class B type I, which are essential for cellular cholesterol homeostasis. The efficiency of cellular cholesterol efflux is determined by the activity of membrane transporters and regulation of their expression, the quantity and quality of extracellular acceptors and so on . Recent advances indicate that conditions locally in the atherosclerotic lesion, including lipids accumulation, inflammation, oxidative stress, hypoxia and insulin resistance, critically influence the expression of cholesterol transporters, which is in line affects the happen and progress of atherosclerosis associated witha change of cholesterol efflux, This review focuses on the current views on the relative roles of different cellular cholesterol efflux pathways, and the regulation on transporters of lipids accumulation, inflammation, oxidative stress, hypoxia and insulin resistance, which often accompany with the happen of atherosclerotic lesion, aiming at providing new theoretical evidence and drug targets to promote the development of therapies on atherosclerosis.

In this study we explored that whether PDE inhibitor rolipram affected cholesrterol efflux and ABCA1 expression in THP-1 macrophage foam cells. Cholesterol efflux in THP-1 macrophage-derived foam cells were detected by FJ-2107P type liquid scintillator. The expression of ABCA1 mRNA and protein were determined by RT-PCR and Western blotting respectively. The levels of cAMP were analysed by low PH EIA. The method of liquid scintillator confirmed PDE inhibitor rolipram promoted cholesterol efflux in THP-1 macrophage foam cells with a time-dependent manner. The results of RT-PCR and Western blotting proved that in THP-1 macrophage-derived foam cells, rolipram increased the levels of ABCA1 mRNA and protein with time, respectively, HPLC testified that rolipram time-dependent decreased the levels of cholesterol and cholesterol ester and upgratulated cAMP in THP-1 macrophage-derived foam cells. Therefore, PDE specific inhibitor rolipram may increase cholesterol efflux and promote ABCA1 expression in THP-1 macrophage-derived foam cells. This study reveals a novel therapy strategy for atherosclerosis.

<正>目的:观察小檗碱对THP-1巨噬细胞源性泡沫细胞ABCA1表达及其细胞内胆固醇流出的影响,并探讨肝X受体去乙酰化在此过程中的作用。方法:用160 nmol/L的佛波酯处理THP-1细胞24 h,使其诱导分化为巨噬细胞,并以50 mg/L的

<正>目的:以对THP-1巨噬细胞源性泡沫细胞为研究对象,观察叔丁基对苯二酚(Tertiary butylhydroquinone,tBHQ)对胞内ABCA1表达的影响,并探讨其作用机制。方法:用real-time PCR和Western blotting方法检测tBHQ处理不同时点及不同浓

Since the inverse relationship between plasma high-density lipoprotein cholesterol (HDL-C) levels and the risk of coronary artery disease (CAD) have been well-established, it has always been a hot spot on how to regulate HDL-C levels for the treatment of CAD-related disease. High and low HDL levels are closely related to its own production and metabolism, which are primarily determined by corresponding regulatory genes. It has been suggested that plasma HDL-C levels have a strong inherited basis with heritability estimates of 40%similar to 60%, showing the great significance in discussing variants causes associated with HDL-C levels. Candidate gene, genome-wide linkage, and most recently genome-wide association (GWA) studies have identified several genetic variations for plasma HDL-C levels. However, the functional role of some variants remains unknown, and they do not always have relation to the risk of CAD. This review will be summarized on the structure of HDL, its metabolism and production, as well as the genetic causes of high and low HDL-C. Notably, recent genetic findings from candidate gene and the GWA studies will be the focus of this text aiming at elucidating the important genetic factors affecting HDL-C concentrations. Comprehensive study on genetics conferring to high and low HDL-C levels using integrative approaches is essential to reveal their relationships with CAD and explore novel pathways on the treatment of CAD.

<正>目的:探讨miR-27a/b对ABCA1及其介导的胆固醇流出的影响。方法:萤光素酶报告基因检测miR-27a/b与ABCA1的结合情况;体外培养THP-1细胞、RAW 264.7细胞和HepG细胞,将miR-27a/b mimics或miR-27a/b inhibitor转染入细

目的本实验通过高脂饮食建立早期高脂血症兔模型,观察普罗布考对胆固醇相关转运体以及炎症因子的影响。方法新西兰白兔36只,雄雌不拘,采用数字表法随机分为基础组(n=9)、基础+普罗布考组(每只77 mg/d,n=9)、高脂组(n=9)和高脂+普罗布考组(每只77 mg/d,n=9)。40天后观察普罗布考对血脂的影响;HE染色观察普罗布考对各组新西兰白兔腹主动脉斑块形成的影响;油红O染色观察普罗布考对各组新西兰白兔肝脏脂质蓄积的影响;定量PCR测定普罗布考对新西兰白兔腹主动脉、肝脏和小肠中胆固醇相关转运体基因表达的影响;Western blot以及免疫组化测定普罗布考对新西兰白兔腹主动脉、肝脏、小肠内胆固醇相关转运蛋白表达的影响;ELISA方法测定普罗布考对炎症因子的影响。结果与基础组相比,高脂组免血清总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)、甘油三酯(TG)水平均明显升高;与高脂组比较,高脂+普罗布考组免血清TC、LDL-C、HDL-C、TG水平均明显下降;高脂组中有动脉斑块形成,肝脏脂质蓄积增多;高脂+普罗布考组中,普罗布考明显抑制斑块的形成,减少肝脏脂质蓄积;普罗布考促进肝脏中ABCG1和SR-BI蛋白及其mRNA的表达,抑制ABCA1蛋白及其mRNA的表达,对SR-A和CD36的表达没有影响;普罗布考抑制炎症因子如IL-6、MCP-1、MCSF、VCAM-1、TNF-α的表达。结论普罗布考抑制ABCA1和炎症因子的表达,促进ABCG1和SR-B1的表达。