摘要：
Macrophage-activating lipopeptide-2 (MALP-2) has been shown to promote the development of atherosclerosis. ATP-binding cassette transporter A1 (ABCA1), a transmembrane protein, plays a critical role in mediating cholesterol export from macrophages to apolipoprotein A-I (apoA-I). However, whether MALP-2 can regulate the expression of ABCA1 is still largely unknown. The aim of this study was to explore the effects of MALP-2 on ABCA1 expression in THP-1 macrophages and the underlying mechanisms. Our results showed that the treatment of cells with MALP-2 decreased ABCA1 level and suppressed cholesterol efflux in both concentration- and time-dependent manners. The contents of intracellular cholesterol were significantly increased in the presence of MALP-2. Moreover, MALP-2-mediated inhibition of ABCA1 expression was abolished by siRNA of either Toll-like receptor 2 (TLR2) or nuclear factor κB (NF-κB). A similar effect was produced by treatment with the NF-κB inhibitor pyrrolidine dithiocarbamate. In addition, MALP-2-induced activation of NF-κB markedly increased zinc finger protein 202 (ZNF202) level, and ZNF202 siRNA impaired the effects of MALP-2 on ABCA1 expression. Taken together, these results suggest that MALP-2 can decrease ABCA1 expression and subsequent cholesterol efflux through activation of the TLR2/NF-κB/ZNF202 signaling pathway in THP-1 macrophages.
作者：
Cui Li-Bao;Yu Xiao-Hua;Jiang Chong-Hui;Tang Ya-Ling;Ouyang Xin-Ping;...
期刊：
生物化学与生物物理进展,2015年42(9):866-876 ISSN：1000-3282
通讯作者：
Tang Chao-Ke
作者机构：
[Ouyang Xin-Ping; Yao Feng; Yu Xiao-Hua; Cui Li-Bao; He Ping-Ping; Tang Chao-Ke; Lu Yun-Cheng; Zhang Min; Tang Ya-Ling] Univ South China, Hunan Prov Cooperat Innovat Ctr Mol Target New Dr, Key Lab Atherosclerol Hunan Prov, Inst Cardiovasc Res,Life Sci Res Ctr, Hengyang 421001, Peoples R China.;[Jiang Chong-Hui; Cui Li-Bao] Cent Hosp Hengyang, Dept Pharm, Hengyang 421001, Peoples R China.
通讯机构：
[Tang Chao-Ke] U;Univ South China, Hunan Prov Cooperat Innovat Ctr Mol Target New Dr, Key Lab Atherosclerol Hunan Prov, Inst Cardiovasc Res,Life Sci Res Ctr, Hengyang 421001, Peoples R China.
关键词：
ABCA1;ABCG5;ABCG8;Atherosclerosis;HDL-C;Inflammation;Probucol;SR-B I
摘要：
Probucol is a potent hypolipidemic drug that decreases plasma high-density lipoprotein cholesterol (HDL-C) levels but attenuates atherosclerosis. However, the detailed mechanisms are not fully understood. The aim of this study was to explore the molecular mechanisms of the HDL-C-lowering and antiatherogenic effects of probucol. New Zealand white rabbits were randomly divided into normal diet group, normal diet+probucol group, high fat diet (HFD) group and HFD+probucol (HFD+P) group. After 7 weeks of treatments, the extent of the atherosclerotic lesions, hepatic lipid accumulation and plasma levels of triglycerides, total cholesterol, low-density lipoprotein cholesterol and HDL-C were significantly reduced in HFD+P group as compared to HFD group. Probucol effectively inhibited down-regulation of hepatic scavenger receptor class B type I (SR-B I) expression, and ATP-binding cassette (ABC) transporters G5 (ABCG5) and G8 (ABCG8) expression in the liver and small intestine induced by HFD but further promoted HFD-induced reduction in hepatic ABC transporter A1 (ABCA1) expression. In addition, probucol also significantly prevented HFD-induced increases of tumor necrosis factor-alpha, interleukin-1, interleukin-6 and monocyte chemotactic protein-1 levels in the aortic arch and plasma. Thus, our data provide strong evidence that probucol alleviates atherosclerosis through regulating ABCA I, SR-B I, ABCG5 and ABCG8 expression and inhibiting the secretion of proinflammatory cytokines in hypercholesterolemic rabbits.
期刊：
MOLECULAR MEDICINE REPORTS,2015年12(3):3599-3606 ISSN：1791-2997
通讯作者：
Yuan, Zhonghua
作者机构：
[Meng, Lei; Tang, Chaoke; Yin, Weidong; Qiao, Yuncheng; Yi, Guanghui; Guo, Dongming; Wang, Zuo; Yuan, Zhonghua] Univ South China, Inst Cardiovasc Dis, Key Lab Arteriosclerol Hunan, Hengyang 421001, Hunan, Peoples R China.;[Qiao, Yuncheng] Pingyu Renmin Hosp, Dept Cardiovasc Med, Pingyu 463400, Henan, Peoples R China.;[Liu, Qingnan] Yiyang Med Coll, Dept Basic Nursing, Yiyang 413000, Hunan, Peoples R China.;[Liu, Xiaohui] Soochow Univ, Cyrus Tang Hematol Ctr Res Partnership, Jiangsu Inst Hematol, Affiliated Hosp 1, Suzhou 215400, Jiangsu, Peoples R China.;[Tian, Guoping] Univ South China, Dept Cardiovasc Med, Affiliated Hosp 2, Hengyang 421001, Hunan, Peoples R China.
通讯机构：
[Yuan, Zhonghua] U;Univ South China, Inst Cardiovasc Dis, Key Lab Arteriosclerol Hunan, 28 West Changsheng Rd, Hengyang 421001, Hunan, Peoples R China.
关键词：
small interfering RNA;adipophilin;acyl-coenzyme A;cholesterol acyltransferse 1;retrovirus;lipid
摘要：
Oxidized low-density lipoprotein (ox-LDL) can increase the expression of adipophilin and the accumulation of intracellular lipid droplets. However, the detailed mechanisms remain to be fully elucidated. The present study aimed to investigate the mechanism underlying the effect of ox-LDL on the expression of adipophilin and the accumulation of intracellular cholesterol esters. The results revealed that ox-LDL increased the activation of protein kinase C alpha (PKC alpha), expression of adipophilin and acyl-coenzymeA: cholesterol acyltransferse 1 (ACAT1) and increased accumulation of intracellular cholesterol esters. In addition, PKCa siRNA abrogated ox-LDL-induced adipophilin, expression of ATAC1 and accumulation of cholesterol esters. Furthermore, ox-LDL increased the accumulation of intracellular cholesterol esters and expression of ACAT1, and this effect were reversed by transfection with adipophilin siRNA. Taken together, these results demonstrated that ox-LDL induces the accumulation of cholesterol esters, which is mediated by the PKC alpha-adipophilin-ACAT1 pathway.
