Mitochondrial (dys)function and.regulation of macrophage cholesterol efflux
Mitochondrial (dys)function and.regulation of macrophage cholesterol efflux
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DOI：
10.1042/cs20120358
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发表时间：
2013-04-01
期刊：
影响因子：
6
通讯作者：
Graham, Annette
中科院分区：
文献类型：
--
作者：
Allen, Anne Marie;Taylor, Janice M. W.;Graham, Annette
胆固醇从线粒体外膜到低胆固醇内膜的运输需要线粒体通电、极化和积极呼吸，由一个高度调控的多聚体(140-200 kDa)蛋白复合体介导，该复合体包括类固醇合成急性调节蛋白(STAR)、线粒体TSPO(转位蛋白)、电压依赖阴离子通道(VDAC)、腺核苷酸转运体(ANT)和相关调节蛋白。线粒体胆固醇的转运在依赖于CYP27A1(甾醇27-羟基酶)的氧固醇配体的LXR(肝X受体)转录因子的产生中是限速的，这些转录因子调节胆固醇外流途径中编码蛋白的基因的表达，例如ABC转运体(ATP结合盒转运体)ABCA1和Abcg1。这些转运体通过质膜将胆固醇和/或磷脂转移到(Apo)脂蛋白受体，产生新生的HDL(高密度脂蛋白)，可以安全地将多余的胆固醇通过血流输送到肝脏，在胆汁中排泄。利用类固醇生成组织的信息，我们认为线粒体功能的紊乱可能会降低胆固醇外流途径的效率，有利于胆固醇酯泡沫细胞的积累，并允许游离胆固醇在内质网和线粒体膜之间的界面上有毒积累。反过来，这将触发通透性转换孔的打开，允许通过CYP27A1不受调节地产生氧固醇，从而允许这种氧化甾醇的酯化形式在人类动脉粥样硬化病变中积累。胆固醇外流缺陷还可诱导内质网应激、ABCA1蛋白酶体降解和Fas依赖的细胞凋亡，复制晚期动脉粥样硬化病变中巨噬细胞的发现。以线粒体为靶点的小分子，能够维持线粒体的功能或改善胆固醇的运输，可能有助于胆固醇从巨噬细胞泡沫细胞中流出，使动脉粥样硬化斑块退化和稳定。
Cholesterol trafficking from the outer to the cholesterol-poor inner mitochondrial membrane requires energized, polarized and actively respiring mitochondria, mediated by a highly regulated multimeric (140-200 kDa) protein complex comprising StAR (steroidogenic acute regulatory protein), mitochondrial TSPO (translocator protein), VDAC (voltage-dependent anion channel), ANT (adenine nucleotide transporter) and associated regulatory proteins. Mitochondrial cholesterol transport is rate-limiting in the CYP27A1 (sterol 27-hydroxylase)-dependent generation of oxysterol ligands for LXR (liver X receptor) transcription factors that regulate the expression of genes encoding proteins in the cholesterol efflux pathway, such as ABC transporters (ATP-binding cassette transporters) ABCA1 and ABCG1. These transporters transfer cholesterol and/or phospholipids across the plasma membrane to (apo)lipoprotein acceptors, generating nascent HDLs (high-density lipoproteins), which can safely transport excess cholesterol through the bloodstream to the liver for excretion in bile. Utilizing information from steroidogenic tissues, we propose that perturbations in mitochondrial function may reduce the efficiency of the cholesterol efflux pathway, favouring accumulation of cholesteryl ester 'foam cells' and allowing the toxic accumulation of free cholesterol at the interface between the endoplasmic reticulum and the mitochondrial membrane. In turn, this will trigger opening of the permeability transition pore, allowing unregulated production of oxysterols via CYP27A1, allowing the accumulation of esterified forms of this oxysterol within human atherosclerotic lesions. Defective cholesterol efflux also induces endoplasmic reticulum stress, proteasomal degradation of ABCA1 and Fas-dependent apoptosis, replicating findings in macrophages in advanced atherosclerotic lesions. Small molecules targeted to mitochondria, capable of sustaining mitochondrial function or improving cholesterol trafficking may aid cholesterol efflux from macrophage 'foam' cells, regressing and stabilizing the atherosclerotic plaque.