Cholesterol Efflux-Independent Modification of Lipid Rafts by AIBP (Apolipoprotein A-I Binding Protein).
Cholesterol Efflux-Independent Modification of Lipid Rafts by AIBP (Apolipoprotein A-I Binding Protein).
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DOI：
10.1161/atvbaha.120.315037
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发表时间：
2020-10
期刊：
影响因子：
--
通讯作者：
Sviridov D
中科院分区：
文献类型：
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作者：
Low H;Mukhamedova N;Capettini LDSA;Xia Y;Carmichael I;Cody SH;Huynh K;Ditiatkovski M;Ohkawa R;Bukrinsky M;Meikle PJ;Choi SH;Field S;Miller YI;Sviridov D
载脂蛋白A-I结合蛋白（Apolipoprotein A-I binding protein， AIBP）是一种有效的、选择性的脂筏调节剂，可调节源自脂筏的多种代谢途径，包括炎症。其作用机制可能涉及AIBP刺激胆固醇外排，消耗脂质筏的胆固醇，这对脂质筏的完整性至关重要。在这里，我们描述了AIBP对脂质筏调节的不同机制。我们证明AIBP对筏的调节可能并不完全取决于胆固醇外排的速率或外排的关键调节因子，ATP结合盒转运蛋白A-I （ABCA1）的存在。AIBP与磷脂酰肌醇3-磷酸相互作用[PI(3)P]，这与Cdc42的丰度增加和活化以及肌动蛋白细胞骨架的重排有关。细胞骨架重排伴随着脂筏丰度的减少，而脂筏的脂质组成没有显著变化。AIBP与PI(3)P的相互作用被AIBP底物NADPH阻断，NADPH和Cdc42的沉默都干扰了AIBP调节脂质筏和胆固醇外排的能力。我们的研究结果表明，AIBP调节脂质筏的潜在机制涉及pip依赖性的细胞骨架重排。
Apolipoprotein A-I binding protein (AIBP) is an effective and selective regulator of lipid rafts modulating many metabolic pathways originating from the rafts, including inflammation. The mechanism of action was suggested to involve stimulation by AIBP of cholesterol efflux, depleting rafts of cholesterol, which is essential for lipid raft integrity. Here we describe a different mechanism contributing to the regulation of lipid rafts by AIBP. We demonstrate that modulation of rafts by AIBP may not exclusively depend on the rate of cholesterol efflux or presence of the key regulator of the efflux, ATP binding cassette transporter A-I (ABCA1). AIBP interacted with phosphatidylinositol 3-phosphate [PI(3)P], which was associated with increased abundance and activation of Cdc42 and re-arrangement of the actin cytoskeleton. Cytoskeleton re-arrangement was accompanied with reduction of the abundance of lipid rafts, without significant changes in the lipid composition of the rafts. The interaction of AIBP with PI(3)P was blocked by AIBP substrate, NADPH, and both NADPH and silencing of Cdc42 interfered with the ability of AIBP to regulate lipid rafts and cholesterol efflux. Our findings indicate that an underlying mechanism of regulation of lipid rafts by AIBP involves PIP-dependent rearrangement of the cytoskeleton.