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Background ApoAI (apolipoproteins AI) and apoAII (apolipoprotein AII) are structural and functional proteins of high-density lipoproteins (HDL) which undergo post-translational modifications at specific residues, creating distinct proteoforms. While specific post-translational modifications have been reported to alter apolipoprotein function, the full spectrum of apoAI and apoAII proteoforms and their associations with cardiometabolic phenotype remains unknown. Herein, we comprehensively characterize apoAI and apoAII proteoforms detectable in serum and their post-translational modifications and quantify their associations with cardiometabolic health indices. Methods and Results Using top-down proteomics (mass-spectrometric analysis of intact proteins), we analyzed paired serum samples from 150 CARDIA (Coronary Artery Risk Development in Young Adults) study participants from year 20 and 25 exams. Measuring 15 apoAI and 9 apoAII proteoforms, 6 of which carried novel post-translational modifications, we quantified associations between percent proteoform abundance and key cardiometabolic indices. Canonical (unmodified) apoAI had inverse associations with HDL cholesterol and HDL-cholesterol efflux, and positive associations with obesity indices (body mass index, waist circumference), and triglycerides, whereas glycated apoAI showed positive associations with serum glucose and diabetes mellitus. Fatty-acid‒modified ApoAI proteoforms had positive associations with HDL cholesterol and efflux, and inverse associations with obesity indices and triglycerides. Truncated and dimerized proteoforms of apoAII were associated with HDL cholesterol (positively) and obesity indices (inversely). Several proteoforms had no significant associations with phenotype. Conclusions Associations between apoAI and AII and cardiometabolic indices are proteoform-specific. These results provide "proof-of-concept" that precise chemical characterization of human apolipoproteins will yield improved insights into the complex pathways through which proteins signify and mediate health and disease.

背景

载脂蛋白 AI（apoAI）和载脂蛋白 AII（apoAII）是高密度脂蛋白（HDL）的结构和功能蛋白，在特定残基上发生翻译后修饰，产生不同的蛋白形式。虽然已经报道了特定的翻译后修饰会改变载脂蛋白的功能，但 apoAI 和 apoAII 蛋白形式的全貌及其与心脏代谢表型的关联仍不清楚。在此，我们全面描述了可在血清中检测到的 apoAI 和 apoAII 蛋白形式及其翻译后修饰，并定量了它们与心脏代谢健康指标的关联。

方法和结果

使用自上而下的蛋白质组学（完整蛋白质的质谱分析），我们分析了来自 CARDIA（年轻人冠状动脉风险发展）研究的 150 名参与者在 20 年和 25 年检查时的配对血清样本。测量了 15 种 apoAI 和 9 种 apoAII 蛋白形式，其中 6 种带有新的翻译后修饰，我们量化了蛋白形式丰度百分比与关键心脏代谢指标之间的关联。未修饰的（未修饰）apoAI 与高密度脂蛋白胆固醇和高密度脂蛋白胆固醇流出呈负相关，与肥胖指数（体重指数、腰围）和甘油三酯呈正相关，而糖化 apoAI 与血清葡萄糖和糖尿病呈正相关。脂肪酸修饰的 apoAI 蛋白形式与高密度脂蛋白胆固醇和流出呈正相关，与肥胖指数和甘油三酯呈负相关。apoAII 的截断和二聚化蛋白形式与高密度脂蛋白胆固醇（阳性）和肥胖指数（阴性）相关。几种蛋白形式与表型无显著关联。