Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospitals, Switzerland; Department of Human Protein Science, Faculty of Medicine, Geneva, Switzerland.
Swiss Med Wkly. 2013 May 25;143:w13781. doi: 10.4414/smw.2013.13781. eCollection 2013.
Apolipoprotein A-1 (apoA-1) is the principal protein fraction of high-density lipoprotein (HDL), conferring to the latter many of its pleiotropic atheroprotective functions. After its effect on cholesterol efflux, the second most studied feature of apoA-1 is its anti-inflammatory property. In addition, it interferes with lipid peroxidation and innate immune receptors. These anti-inflammatory effects are due to various properties, in particular the ability to inhibit the transendothelial migration of immune cells by reducing integrin expression, to inhibit monocyte activation and cytokine production induced by T-cell contact, to inhibit lipid peroxidation and to interfere with innate immune receptors. Recent studies have demonstrated that during chronic systemic inflammation HDL could lose some of its atheroprotective functions and become dysfunctional or even proinflammatory. Recent evidence suggests that specific post-translational modifications of apoA-1 transform this genuine anti-inflammatory molecule into a proinflammatory one. The structural changes include chlorination, nitration and carbamylation of amino acids by myeloperoxidase, oxidation by reactive carbonyls, as well as glycation. Humoral autoimmunity to apoA-1 and HDL has been reported in populations at high cardiovascular risk and constitutes another emerging mechanism contributing to the loss of functions of apoA-1 and HDL. The fact that in recent trials cholesteryl ester transfer protein inhibitors (torcerapib and dalcetrapib) have unfortunately failed to prevent cardiovascular disease despite increasing cholesterol efflux in vitro and HDL levels in vivo, further highlights the clinical importance of understanding the mechanisms driving apoA-1 and HDL towards pro- or anti-inflammatory molecules. These findings should not affect current dyslipidaemia management guidelines.
载脂蛋白 A-1（apoA-1）是高密度脂蛋白（HDL）的主要蛋白部分，赋予后者许多多效性的抗动脉粥样硬化功能。除了对胆固醇外流的影响外，apoA-1 的第二个研究最多的特征是其抗炎特性。此外，它还干扰脂质过氧化和先天免疫受体。这些抗炎作用归因于多种特性，特别是通过降低整合素表达抑制免疫细胞的跨内皮迁移、抑制 T 细胞接触诱导的单核细胞激活和细胞因子产生、抑制脂质过氧化和干扰先天免疫受体的能力。最近的研究表明，在慢性全身炎症期间，HDL 可能会失去其一些抗动脉粥样硬化功能，变得功能失调甚至促炎。最近的证据表明，apoA-1 的特定翻译后修饰将这种真正的抗炎分子转化为促炎分子。结构变化包括髓过氧化物酶对氨基酸的氯化、硝化和氨甲酰化、活性羰基的氧化以及糖基化。在心血管风险较高的人群中已经报道了针对 apoA-1 和 HDL 的体液自身免疫，这是导致 apoA-1 和 HDL 功能丧失的另一个新兴机制。在最近的试验中，胆固醇酯转移蛋白抑制剂（torcerapib 和 dalcetrapib）不幸未能预防心血管疾病，尽管体外增加了胆固醇外流和体内 HDL 水平，这进一步强调了了解驱动 apoA-1 和 HDL 向促炎或抗炎分子发展的机制的临床重要性。这些发现不应影响当前的血脂异常管理指南。
