Apolipoprotein E4 is deficient in inducing macrophage ABCA1 expression and stimulating the Sp1 signaling pathway.
Apolipoprotein E4 is deficient in inducing macrophage ABCA1 expression and stimulating the Sp1 signaling pathway.
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DOI：
10.1371/journal.pone.0044430
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Yang H
中科院分区：
文献类型：
--
作者：
Okoro EU;Zhao Y;Guo Z;Zhou L;Lin X;Yang H
ATP结合盒A1（ABCA1）是促进细胞胆固醇流出的膜蛋白。使用RAW 264.7巨噬细胞，我们研究了载脂蛋白（apo）E3和apoE4对ABCA 1和调节其表达的信号通路的相对影响。脂质相关和无脂质apoE4形式诱导的ABCA 1蛋白和mRNA水平比apoE3形式低约30%。与apoE3相比，apoE4处理时，磷酸肌醇3-激酶（PI3K）、蛋白激酶C β（PKC β）和特异性蛋白1（Sp1）的磷酸化水平也较低。在人THP-1单核细胞/巨噬细胞中证实了apoE4诱导ABCA 1表达、PKC β 1和Sp1磷酸化的能力降低。PI3K、PKC β和Sp1的顺序磷酸化被认为是ABCA 1表达上调的机制。apoE3和apoE4都能降低载脂RAW 264.7细胞中的总胆固醇和胆固醇酯，并诱导apoAI介导的胆固醇流出。然而，与apoE3处理的细胞相比，apoE4处理的细胞中的胆固醇酯和胆固醇流出分别低约50%和约24%。胆固醇酯在巨噬细胞中的积聚是泡沫细胞形成的机制。因此，apoE4激活PI3K-PKC β-Sp1信号通路和诱导ABCA 1表达的能力降低可能损害胆固醇酯的去除，并增加泡沫细胞的形成。
ATP binding cassette A1 (ABCA1) is a membrane protein that promotes cellular cholesterol efflux. Using RAW 264.7 macrophages, we studied the relative effects of apolipoprotein (apo) E3 and apoE4 on ABCA1 and on the signaling pathway that regulates its expression. Both lipid-associated and lipid-free apoE4 forms induced ∼30% lower levels of ABCA1 protein and mRNA than apoE3 forms. Phosphorylated levels of phosphoinositol 3-kinase (PI3K), protein kinase Cζ (PKCζ) and specificity protein 1 (Sp1) were also lower when treated with apoE4 compared to apoE3. The reduced ability of apoE4 to induce ABCA1 expression, PKCζ and Sp1 phosphorylation were confirmed in human THP-1 monocytes/macrophages. Sequential phosphorylation of PI3K, PKCζ and Sp1 has been suggested as a mechanism for upregulation of ABCA1 expression. Both apoE3 and apoE4 reduced total cholesterol and cholesterol esters in lipid-laden RAW 264.7 cells, and induced apoAI-mediated cholesterol efflux. However, the cholesterol esters and cholesterol efflux in apoE4-treated cells were ∼50% and ∼24% lower, respectively, compared to apoE3-treated cells. Accumulation of cholesterol esters in macrophages is a mechanism for foam cell formation. Thus the reduced ability of apoE4 to activate the PI3K-PKCζ-Sp1 signaling pathway and induce ABCA1 expression likely impairs cholesterol ester removal, and increases foam cell formation.
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DOI：
10.1161/01.atv.0000193627.12516.1d
发表时间：
2006-01-01
影响因子：
8.7
作者：
Huang, ZH;Fitzgerald, ML;Mazzone, T
通讯作者：
Mazzone, T
影响因子：
15.1
作者：
Gong JS;Morita SY;Kobayashi M;Handa T;Fujita SC;Yanagisawa K;Michikawa M
通讯作者：
Michikawa M
DOI：
10.1073/pnas.78.12.7545
发表时间：
1981-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
BASU, SK;BROWN, MS;GOLDSTEIN, JL
通讯作者：
GOLDSTEIN, JL
DOI：
10.1073/pnas.80.1.283
发表时间：
1983-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
BLUE, ML;WILLIAMS, DL;BLUM, CB
通讯作者：
BLUM, CB
DOI：
10.1161/01.atv.4.5.452
发表时间：
1984-01-01
期刊：
ARTERIOSCLEROSIS
影响因子：
--
作者：
FUNKE, H;BOYLES, J;MAHLEY, RW
通讯作者：
MAHLEY, RW