High-density lipoprotein proteome dynamics in human endotoxemia
High-density lipoprotein proteome dynamics in human endotoxemia
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DOI：
10.1186/1477-5956-9-34
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发表时间：
2011-06-28
期刊：
影响因子：
2
通讯作者：
Meijers, Joost C. M.
中科院分区：
文献类型：
--
作者：
Levels, Johannes H. M.;Geurts, Pierre;Meijers, Joost C. M.
背景资料：参与炎症、凝血、脂质氧化和脂质代谢的多种蛋白质与高密度脂蛋白（HDL）相关，预计HDL蛋白质组的变化对HDL的多种功能有影响。在这里，SELDI-TOF质谱（MS）被用来研究在人类实验性低剂量内毒素血症模型中HDL蛋白组成的动态变化。10名HDL胆固醇水平低（0.7+/-0.1 mmol/L）和10名HDL胆固醇水平高（1.9+/-0.4 mmol/L）的健康男性静脉注射内毒素（LPS）（1 ng/kg体重）。我们以前的研究表明，低HDL胆固醇的受试者更容易受到炎症的影响。目前的研究测试的假设，这种差异可能与HDL proteome.Results的差异：血浆在7个时间点在LPS挑战后的24小时内抽取用于直接捕获HDL使用载脂蛋白A-I抗体，随后由随后的SELDI-TOF MS分析。在LPS施用后，在两个研究组中的蛋白质组中观察到21种标志物的显著变化（调整的p值< 0.05）。这些变化在LPS输注后1小时观察到，并持续长达24小时，但出乎意料的是，两个研究组之间没有差异。所有个体在所有时间点的蛋白质谱的层次聚类显示3个不同的簇，这在很大程度上独立于基线HDL胆固醇水平，但与对氧磷酶1活性相关。急性时相蛋白血清淀粉样蛋白A-1/2（SAA-1/2）明显上调后，LPS输注在两个组，包括天然和N-末端截短的变体，通过二维凝胶电泳和质谱鉴定。个体的一个集群的区别较低的SAA-1/ 2响应LPS的挑战和延迟的时间响应的截断variants.Conclusions：这项研究表明，半定量的差异，在HDL蛋白质组的SELDI-TOF MS评估不能解释为什么低HDL胆固醇的受试者更容易受到LPS的挑战比那些高HDL胆固醇。相反，结果表明，分层聚类可能是有用的，以预测HDL功能的急性期对LPS的反应。
Background: A large variety of proteins involved in inflammation, coagulation, lipid-oxidation and lipid metabolism have been associated with high-density lipoprotein (HDL) and it is anticipated that changes in the HDL proteome have implications for the multiple functions of HDL. Here, SELDI-TOF mass spectrometry (MS) was used to study the dynamic changes of HDL protein composition in a human experimental low-dose endotoxemia model. Ten healthy men with low HDL cholesterol (0.7+/-0.1 mmol/L) and 10 men with high HDL cholesterol levels (1.9+/-0.4 mmol/L) were challenged with endotoxin (LPS) intravenously (1 ng/kg bodyweight). We previously showed that subjects with low HDL cholesterol are more susceptible to an inflammatory challenge. The current study tested the hypothesis that this discrepancy may be related to differences in the HDL proteome.Results: Plasma drawn at 7 time-points over a 24 hour time period after LPS challenge was used for direct capture of HDL using antibodies against apolipoprotein A-I followed by subsequent SELDI-TOF MS profiling. Upon LPS administration, profound changes in 21 markers (adjusted p-value < 0.05) were observed in the proteome in both study groups. These changes were observed 1 hour after LPS infusion and sustained up to 24 hours, but unexpectedly were not different between the 2 study groups. Hierarchical clustering of the protein spectra at all time points of all individuals revealed 3 distinct clusters, which were largely independent of baseline HDL cholesterol levels but correlated with paraoxonase 1 activity. The acute phase protein serum amyloid A-1/2 (SAA-1/2) was clearly upregulated after LPS infusion in both groups and comprised both native and N-terminal truncated variants that were identified by two-dimensional gel electrophoresis and mass spectrometry. Individuals of one of the clusters were distinguished by a lower SAA-1/ 2 response after LPS challenge and a delayed time-response of the truncated variants.Conclusions: This study shows that the semi-quantitative differences in the HDL proteome as assessed by SELDI-TOF MS cannot explain why subjects with low HDL cholesterol are more susceptible to a challenge with LPS than those with high HDL cholesterol. Instead the results indicate that hierarchical clustering could be useful to predict HDL functionality in acute phase responses towards LPS.