HDL and innate immunity: a tale of two apolipoproteins11 See referenced articles, J. Lipid Res. 2008, 49: 1640–1645 and 1782–1793.
HDL and innate immunity: a tale of two apolipoproteins11 See referenced articles, J. Lipid Res. 2008, 49: 1640–1645 and 1782–1793.
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DOI：
10.1194/jlr.e800011-jlr200
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发表时间：
2008-08
影响因子：
6.5
通讯作者：
C. Grunfeld;K. Feingold
中科院分区：
文献类型：
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作者：
C. Grunfeld;K. Feingold
除了公认的脂蛋白转运功能外，大量证据表明，脂蛋白作为先天免疫系统的一部分，在宿主防御中也起着重要作用（回顾，参见参考文献1）。其中一个关键的防御功能是HDL和其他脂蛋白结合内毒素（脂多糖，LPS）和其他细菌产物并中和它们的毒性作用的能力。在这一期的Journal of脂质研究中，Wang等人(2)提出了载脂蛋白A-I中和LPS的结构要求。载脂蛋白A-I的螺旋结构基于8个相似的22个氨基酸和2个11个氨基酸串联重复序列，但HDL形成和功能所需的区域现在可以归因于基于特定突变研究的特定区域(3)。中心区域（氨基酸144-186）激活LCAT并促进HDL的成熟和稳定。N（44-65）和C（220-241）末端重复序列是启动脂质结合、形成新生HDL和从巨噬细胞中去除胆固醇所必需的。c端区域（190-243）的大部分对磷脂结合和促进胆固醇外排至关重要。载脂蛋白A-I中自然发生的半胱氨酸突变，如a - ilano和A-IParis，即使在高密度脂蛋白胆固醇水平降低时也能预防动脉粥样硬化(4)。Wang等人的论文(2)通过用其他氨基酸取代特定的半胱氨酸残基，阐述了载脂蛋白A-I的哪些区域是中和LPS所必需的。c端区域的一个半胱氨酸（228）的丝氨酸替换显著降低了HDL中和LPS的能力，而另一个c端替换（195），靠近最后22个残基重复序列，几乎没有影响。中间区域替换（半胱氨酸107、129和173）也没有什么影响。另一方面，第一个n端重复序列（半胱氨酸52）的取代，特别是下一个区域（半胱氨酸74）的取代形成HDL，更有效地中和LPS并保护LPS诱导的肺损伤。因此，Wang等人(2)已经证明，与胆固醇和磷脂代谢一样，载脂蛋白A-I的特定区域对LPS中和至关重要。此外，参与脂多糖中和的区域与参与胆固醇和磷脂代谢的区域不同。例如，这些作者先前已经证明(5)，半胱氨酸残基129和195的替换会损害脂质结合，而在173和195的替换会损害HDL促进胆固醇外排的能力。相比之下，在107取代有增加的能力，促进胆固醇外排。如上所述，52和74处的替换增强了HDL中和LPS的能力，但这些替换对HDL的结构或HDL从巨噬细胞中去除胆固醇的能力没有影响。因此，LPS保护作用的增加使得52和74替代“超级”载脂蛋白A-Is用于宿主防御，对胆固醇逆向转运和增加动脉粥样硬化风险几乎没有不利影响。类似的自然突变是否会在人类中发生，以及载脂蛋白a - i的这种突变是否会在革兰氏阴性感染期间产生有益影响，仍有待观察。此外，研究应该检查载脂蛋白A-I的类似修饰是否也会增强其他有毒细菌产物的中和作用，如脂磷胆酸。感染激活toll样受体，刺激细胞因子的分泌，对脂质和脂蛋白代谢有深远的影响（回顾，见参考文献1）。脂质和脂蛋白代谢的变化是急性期反应（APR）的一部分，这种模式最著名的是血清蛋白的增加(6)。阳性APR蛋白是指在APR期间循环水平升高而阴性APR蛋白下降的蛋白。两种阳性的APR蛋白，c反应蛋白和血清淀粉样蛋白A，与脂蛋白结合，因此可以认为是载脂蛋白。APR期间血清蛋白的增加是转录介导的，通常由NF-kB和NF-IL-6应答元件的转录激活驱动(6)。然而，许多脂质和脂蛋白代谢的变化是部分阴性的
In addition to the well-recognized transport function of lipoproteins, a large body of evidence has demonstrated that lipoproteins also play an important role in host defense as part of the innate immune system (for review, see Ref. 1). One of the key defensive functions is the ability of HDL and other lipoproteins to bind endotoxin (lipopolysaccharide, LPS) and other bacterial products and neutralize their toxic effects. In this issue of the Journal of Lipid Research, Wang et al. (2) provide insights into the structural requirements for LPS neutralization by apolipoprotein A-I. The helical structure of apolipoprotein A-I is based on eight similar 22 amino acid and two 11 amino acid tandem repeats, but the areas required for HDL formation and function can now be attributed to specific regions based on studies of specific mutations (3). The central region (amino acids 144–186) activates LCAT and contributes to HDL maturation and stability. The N(44–65) and C(220–241) terminal repeats are necessary to initiate lipid binding, form nascent HDL, and remove cholesterol from macrophages. A larger portion of the C-terminal region (190–243) is critical for phospholipid binding and promoting cholesterol efflux. Naturally occurring mutations of cysteines in apolipoprotein A-I, such as A-IMilano and A-IParis, are associated with protection against atherosclerosis even when HDL cholesterol levels are decreased (4). The paper by Wang et al. (2) addresses what regions of apolipoprotein A-I are required for neutralization of LPS by substituting other amino acids for specific cysteine residues. Serine substitution of one cysteine (228) in the C-terminal domain dramatically reduced the ability of HDL to neutralize LPS, while another C-terminal substitution (cysteine 195), proximal to the last 22 residue repeat, had little effect. Midregion substitutions (cysteines 107, 129, and 173) also had little effect. On the other hand, substitution in the first N-terminal repeat (cysteine 52) and especially the next region (cysteine 74) formed HDL that was more effective at neutralizing LPS and protecting from LPS induced lung injury. Thus, Wang et al. (2) have shown that, as with cholesterol and phospholipid metabolism, specific regions of apolipoprotein A-I are essential for LPS neutralization. Furthermore, the regions involved in LPS neutralization are different than those involved in cholesterol and phospholipid metabolism. For example, these authors have previously shown (5) that substitution for cysteine residues 129 and 195 impaired lipid binding, while substitutions at 173 and 195 impaired the ability of HDL to promote cholesterol efflux. In contrast, a substitution at 107 had an increased capacity to promote cholesterol efflux. As noted above, the substitutions at 52 and 74 enhanced the ability of HDL to neutralize LPS, yet these substitutions had no effect on HDL structure or the ability of HDL to remove cholesterol from macrophages. Consequently, the increase in protection from LPS makes the 52 and 74 substitutions “super” apolipoproteins A-Is for host defense, with little downside in adversely affecting reverse cholesterol transport and increasing the risk of atherosclerosis. It remains to be seen whether similar naturally occurring mutations occur in humans and whether such mutations in apolipoprotein A-I will have a beneficial effect during gram-negative infections. Additionally, studies should examine whether similar modifications of apolipoprotein A-I will also enhance the neutralization of other toxic bacterial products, such as lipoteichoic acid. Infections activate Toll-like receptors stimulating the secretion of cytokines, which have profound effects on lipid and lipoprotein metabolism (for review, see Ref. 1). The changes in lipid and lipoprotein metabolism are part of the acute phase response (APR), a pattern best known for increases in serum proteins (6). Positive APR proteins are those whose circulating levels increase during the APR while negative APR proteins decrease. Two positive APR proteins, C-reactive protein and serum amyloid A, bind to lipoproteins and hence can be considered to be apolipoproteins. The increases in serum proteins during the APR are transcriptionally mediated and usually driven by activation of transcription at NF-kB and NF-IL-6 response elements (6). However, many of the changes in lipid and lipoprotein metabolism are part of the negative