Effects of Toxicologically Relevant Xenobiotics and the Lipid-Derived Electrophile 4-Hydroxynonenal on Macrophage Cholesterol Efflux: Silencing Carboxylesterase 1 Has Paradoxical Effects on Cholesterol Uptake and Efflux

文献类型： 外文期刊

第一作者： Ross, Matthew K.

作者： Ross, Matthew K.;Borazjani, Abdolsamad;Mangum, Lee C.;Crow, J. Allen;Wang, Ran

作者机构：

期刊名称：CHEMICAL RESEARCH IN TOXICOLOGY （ 影响因子：3.739； 五年影响因子：4.142 ）

ISSN： 0893-228X

年卷期： 2014 年 27 卷 10 期

页码：

收录情况： SCI

摘要： Cholesterol cycles between free cholesterol (unesterified) found predominantly in membranes and cholesteryl esters (CEs) stored 4,001,01, in cytoplasmic lipid droplets. Only free cholesterol is et:fluxed from macrophages via ATP-binding cassette (ABC) transporters to extracellular acceptors Carboxylesterase 1 (CES1), proposed to hydrolyze CEs, is inactivated by oxon metabolites of organophosphorus pesticides and by the lipid electrophile 4-hydroxynonenal (HNE). We assessed the ability of these compounds to reduce cholesterol efflux from foam cells. Human THP-1 macrophages were loaded with [H-3] -cholesterol/acetylated LDL, and then allowed to equilibrate to enable [H-3] cholesterol to distribute into its various cellular pools. The cholesterol-engorged cells were then treated with toxicants in the absence of cholesterol acceptors for 24 h, followed by a 24 h efflux period in the presence of toxicant. A concentration dependent reduction in [3H] cholesterol efflux via ABCA1 (up to 50%) was found for paraoxon (0.1-10 mu M), whereas treatment with HNE had no effect. A modest reduction in [31]cholesterol efflux via ABCG1 (25%) was found after treatment with either paraoxon or chlorpyrifos oxon (10 mu M each) but not HNE. No difference in efflux rates was found after treatments with either paraoxon or HNE when the universal cholesterol acceptor 10% (v/v) fetal bovine serum was used 'When the re-esterification arm of the CE cycle was disabled in foam cells, paraoxon treatment increased CE levels, suggesting the neutral CE hydrolysis arm of the cycle had been inhibited by the toxicant. However, paraoxon also partially inhibited lysosomal acid lipase, which generates cholesterol for efflux, and reduced the expression of ABCA1 protein. Paradoxically, silencing CES1 expression in macrophages did not affect the percent of [314]cholesterol efflux. However, CES1 inRNA knockdown markedly reduced cholesterol uptake by macrophages, with SR-A and CD36 mRNA reduced 3- and 4-fold, respectively. Immunoblots confirmed SR -A and CD36 protein downregulation.

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