Jin Xueting, Sviridov Denis, Liu Ying, Vaisman Boris, Addadi Lia, Remaley Alan T, Kruth Howard S
From the Experimental Atherosclerosis Section (X.J., Y.L., H.S.K.) and Lipoprotein Metabolism Section (D.S., B.V., A.T.R.), National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD; and Department of Structural Biology, Weizmann Institute of Science, Rehovot, Israel (L.A.).
Arterioscler Thromb Vasc Biol. 2016 Dec;36(12):2283-2291. doi: 10.1161/ATVBAHA.116.308334. Epub 2016 Oct 6.
We examined the function of ABCA1 (ATP-binding cassette transporter A1) in ApoA-I (apolipoprotein A-I) mobilization of cholesterol microdomains deposited into the extracellular matrix by cholesterol-enriched macrophages. We have also determined whether an ApoA-I mimetic peptide without and with complexing to sphingomyelin can mobilize macrophage-deposited cholesterol microdomains.
Extracellular cholesterol microdomains deposited by cholesterol-enriched macrophages were detected with a monoclonal antibody, 58B1. ApoA-I and an ApoA-I mimetic peptide 5A mobilized cholesterol microdomains deposited by ABCA1 macrophages but not by ABCA1 macrophages. In contrast, ApoA-I mimetic peptide 5A complexed with sphingomyelin could mobilize cholesterol microdomains deposited by ABCA1 macrophages.
Our findings show that a unique pool of extracellular cholesterol microdomains deposited by macrophages can be mobilized by both ApoA-I and an ApoA-I mimetic peptide but that mobilization depends on macrophage ABCA1. It is known that ABCA1 complexes ApoA-I and ApoA-I mimetic peptide with phospholipid, a cholesterol-solubilizing agent, explaining the requirement for ABCA1 in extracellular cholesterol microdomain mobilization. Importantly, ApoA-I mimetic peptide already complexed with phospholipid can mobilize macrophage-deposited extracellular cholesterol microdomains even in the absence of ABCA1.
我们研究了ATP结合盒转运蛋白A1（ABCA1）在载脂蛋白A-I（ApoA-I）动员由富含胆固醇的巨噬细胞沉积到细胞外基质中的胆固醇微区方面的功能。我们还确定了一种未与鞘磷脂复合以及与鞘磷脂复合后的ApoA-I模拟肽是否能够动员巨噬细胞沉积的胆固醇微区。
用单克隆抗体58B1检测由富含胆固醇的巨噬细胞沉积的细胞外胆固醇微区。ApoA-I和ApoA-I模拟肽5A能够动员ABCA1⁺巨噬细胞沉积的胆固醇微区，但不能动员ABCA1⁻巨噬细胞沉积的胆固醇微区。相比之下，与鞘磷脂复合的ApoA-I模拟肽5A能够动员ABCA1⁻巨噬细胞沉积的胆固醇微区。
我们的研究结果表明，巨噬细胞沉积的独特细胞外胆固醇微区池可被ApoA-I和ApoA-I模拟肽动员，但动员取决于巨噬细胞ABCA1。已知ABCA1将ApoA-I和ApoA-I模拟肽与磷脂（一种胆固醇增溶剂）复合，这解释了细胞外胆固醇微区动员中对ABCA1的需求。重要的是，即使在没有ABCA1的情况下，已经与磷脂复合的ApoA-I模拟肽也能够动员巨噬细胞沉积的细胞外胆固醇微区。
