Defective functionality of HDL particles in familial apoA-I deficiency: relevance of alterations in HDL lipidome and proteome
Defective functionality of HDL particles in familial apoA-I deficiency: relevance of alterations in HDL lipidome and proteome
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DOI：
10.1194/jlr.m051631
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发表时间：
2014-12-01
影响因子：
6.5
通讯作者：
Kontush, Anatol
中科院分区：
文献类型：
--
作者：
Rached, Fabiana;Santos, Raul D.;Kontush, Anatol
为了评价来自遗传性apoA-I缺陷家系的受试者中HDL的功能和组成特性，招募了在APOA 1密码子-2（Q[-2]X）处具有无义突变的2个纯合子和6个杂合子以及年龄和性别匹配的健康对照（n = 11）。纯合子显示血浆apoA-I水平不可检测，HDL-胆固醇（HDL-C）和apoC-III水平降低（分别为对照组的5.4%和42.6%）。杂合子表现出低HDL-C（21 +/- 9 mg/dl）、低apoA-I（79 +/- 24 mg/dl）、正常LDL-胆固醇（132 +/- 25 mg/dl）和升高的TG（130 +/- 45 mg/dl）水平。与对照组相比，杂合子中超离心分离的HDL亚群的胆固醇流出能力降低（高达-25%，P < 0.01，基于甘油磷脂[GP]）。与对照组相比，来自杂合子的小而密的HDL 3和总HDL表现出降低的抗氧化活性（高达-48%，P < 0.001，基于总质量）。HDL亚群从纯合子和杂合子显示改变的化学成分，在apoA-I，GP和胆固醇酯耗尽;富集在apoA-II，游离胆固醇，和TG;和改变磷酸鞘脂。HDL的动脉粥样硬化保护活性的缺陷与脂质和载脂蛋白组成的改变有关。这些数据表明，HDL颗粒的动脉粥样硬化保护活性受损的纯合子和杂合子apoA-I缺陷，并密切相关的蛋白质和脂质组成的显着改变。
To evaluate functional and compositional properties of HDL in subjects from a kindred of genetic apoA-I deficiency, two homozygotes and six heterozygotes, with a nonsense mutation at APOA1 codon -2, Q[-2]X, were recruited together with age- and sex-matched healthy controls (n = 11). Homozygotes displayed undetectable plasma levels of apoA-I and reduced levels of HDL-cholesterol (HDL-C) and apoC-III (5.4% and 42.6% of controls, respectively). Heterozygotes displayed low HDL-C (21 +/- 9 mg/dl), low apoA-I (79 +/- 24 mg/dl), normal LDL-cholesterol (132 +/- 25 mg/dl), and elevated TG (130 +/- 45 mg/dl) levels. Cholesterol efflux capacity of ultracentrifugally isolated HDL subpopulations was reduced (up to -25%, P < 0.01, on a glycerophospholipid [GP] basis) in heterozygotes versus controls. Small, dense HDL3 and total HDL from heterozygotes exhibited diminished antioxidative activity (up to -48%, P < 0.001 on a total mass basis) versus controls. HDL subpopulations from both homozygotes and heterozygotes displayed altered chemical composition, with depletion in apoA-I, GP, and cholesteryl ester; enrichment in apoA-II, free cholesterol, and TG; and altered phosphosphingolipidome. The defective atheroprotective activities of HDL were correlated with altered lipid and apo composition. These data reveal that atheroprotective activities of HDL particles are impaired in homozygous and heterozygous apoA-I deficiency and are intimately related to marked alterations in protein and lipid composition.