Cell lipid metabolism modulators 2-bromopalmitate, D609, monensin, U18666A and probucol shift discoidal HDL formation to the smaller-sized particles: implications for the mechanism of HDL assembly.
Cell lipid metabolism modulators 2-bromopalmitate, D609, monensin, U18666A and probucol shift discoidal HDL formation to the smaller-sized particles: implications for the mechanism of HDL assembly.
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细胞脂质代谢调节剂 2-溴棕榈酸酯、D609、莫能菌素、U18666A 和普罗布考将盘状 HDL 形成转变为较小尺寸的颗粒：对 HDL 组装机制的影响。
DOI：
10.1016/j.bbalip.2016.09.017
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Lyssenko,NicholasN
中科院分区：
文献类型：
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作者：
Quach,Duyen;Vitali,Cecilia;La,FionaM;Xiao,AngelX;Millar,JohnS;Tang,Chongren;Rader,DanielJ;Phillips,MichaelC;Lyssenko,NicholasN
atp结合盒转运蛋白A1 （ABCA1）介导细胞脂质和无脂载脂蛋白A-I （apo A-I）形成盘状高密度脂蛋白（HDL）。盘状高密度脂蛋白颗粒在物理化学特性上是不均匀的，原因尚不完全清楚。盘状脂蛋白颗粒与细胞形成的盘状高密度脂蛋白具有相似的特征和异质性，可以通过无细胞的物理化学方法从纯化的脂质和载脂蛋白A-I中重建。重构HDL （rHDL）的异质性对起始脂质/载脂蛋白A-I混合物的脂质组成敏感。为了确定细胞形成的高密度脂蛋白的异质性是否对细胞脂质的变化同样敏感，我们研究了四种化合物，这些化合物对细胞脂质代谢和abca1介导的细胞胆固醇外排有明确的影响。2-溴铝酸酯、D609、莫能菌素和U18666A减少了大尺寸HDL的形成，但显著增加了小尺寸HDL的形成。2-溴铝酸酯似乎不影响ABCA1活性、亚细胞定位或寡聚化，但诱导了质膜中胆固醇-磷脂复合物的溶解。花生四烯酸和亚油酸将高密度脂蛋白的形成转移到较小的物种。丹吉尔病突变和ABCA1活性抑制剂小麦胚芽凝集素和AG 490减少了大尺寸和小尺寸HDL的形成。普罗布考的效果与2-溴铝酸酯相似。以rHDL的形成为范例，我们提出ABCA1突变和活性抑制剂减少了可用于HDL形成的细胞脂质数量，2-溴铝酸酯基团和多不饱和脂肪酸中的化合物改变了细胞脂质组成，从有利于形成较大尺寸的HDL颗粒转变为有利于形成较小尺寸的物种。
ATP-binding cassette transporter A1 (ABCA1) mediates formation of disc-shaped high-density lipoprotein (HDL) from cell lipid and lipid-free apolipoprotein A-I (apo A-I). Discoidal HDL particles are heterogeneous in physicochemical characteristics for reasons that are understood incompletely. Discoidal lipoprotein particles similar in characteristics and heterogeneity to cell-formed discoidal HDL can be reconstituted from purified lipids and apo A-I by cell-free, physicochemical methods. The heterogeneity of reconstituted HDL (rHDL) is sensitive to the lipid composition of the starting lipid/apo A-I mixture. To determine whether the heterogeneity of cell-formed HDL is similarly sensitive to changes in cell lipids, we investigated four compounds that have well-established effects on cell lipid metabolism and ABCA1-mediated cell cholesterol efflux. 2-Bromopalmitate, D609, monensin and U18666A decreased formation of the larger-sized, but dramatically increased formation of the smaller-sized HDL. 2-Bromopalmitate did not appear to affect ABCA1 activity, subcellular localization or oligomerization, but induced dissolution of the cholesterol-phospholipid complexes in the plasma membrane. Arachidonic and linoleic acids shifted HDL formation to the smaller-sized species. Tangier disease mutations and inhibitors of ABCA1 activity wheat germ agglutinin and AG 490 reduced formation of both larger-sized and smaller-sized HDL. The effect of probucol was similar to the effect of 2-bromopalmitate. Taking rHDL formation as a paradigm, we propose that ABCA1 mutations and activity inhibitors reduce the amount of cell lipid available for HDL formation, and the compounds in the 2-bromopalmitate group and the polyunsaturated fatty acids change cell lipid composition from one that favors formation of the larger-sized HDL particles to one that favors formation of the smaller-sized species.