High density lipoprotein (HDL) particles from end-stage renal disease patients are defective in promoting reverse cholesterol transport
High density lipoprotein (HDL) particles from end-stage renal disease patients are defective in promoting reverse cholesterol transport
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DOI：
10.1038/srep41481
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发表时间：
2017-02-02
影响因子：
4.6
通讯作者：
Tietge, Uwe J. F.
中科院分区：
文献类型：
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作者：
Anderson, Josephine L. C.;Gautier, Thomas;Tietge, Uwe J. F.
动脉粥样硬化性心血管疾病（CVD）是终末期肾病（ESRD）死亡的最大原因。 ESRD 中的 CVD 不能用经典的 CVD 危险因素来解释，例如高密度脂蛋白胆固醇质量水平，使得脂蛋白的功能改变成为可能。 HDL 通过促进胆固醇逆向转运 (RCT) 发挥动脉粥样硬化保护作用，包括胆固醇从巨噬细胞泡沫细胞流出、摄取到肝细胞中并最终排泄到粪便中。将 ESRD-HDL (n = 15) 与健康对照 HDL (n = 15) 进行比较，比较其促进体外 (i) THP-1 巨噬细胞泡沫细胞中胆固醇流出和 (ii) SR-BI 介导的 ldla[SR-BI] 细胞选择性摄取以及 (iii) 体内 RCT 的能力。与对照组的 HDL 相比，ESRD-HDL 在介导的胆固醇流出 (p < 0.001) 和 SR-BI 介导的选择性摄取 (p < 0.01) 方面表现出显着减少，这是 RCT 中的两个关键步骤。一致的是，当输注到野生型小鼠体内时，ESRD-HDL 促进 RCT 的体内能力也显着受损（p < 0.01）。用次氯酸对健康对照的 HDL 进行体外氧化能够完全模拟 ESRD-HDL 受损的生物活性。总之，我们证明 ESRD 患者的 HDL 在关键步骤以及整体 RCT 中功能失调，可能是由于氧化修饰所致。
Atherosclerotic cardiovascular disease (CVD) represents the largest cause of mortality in end-stage renal disease (ESRD). CVD in ESRD is not explained by classical CVD risk factors such as HDL cholesterol mass levels making functional alterations of lipoproteins conceivable. HDL functions in atheroprotection by promoting reverse cholesterol transport (RCT), comprising cholesterol efflux from macrophage foam cells, uptake into hepatocytes and final excretion into the feces. ESRD-HDL (n = 15) were compared to healthy control HDL (n = 15) for their capacity to promote in vitro (i) cholesterol efflux from THP-1 macrophage foam cells and (ii) SR-BI-mediated selective uptake into ldla[SR-BI] cells as well as (iii) in vivo RCT. Compared with HDL from controls, ESRD-HDL displayed a significant reduction in mediating cholesterol efflux (p < 0.001) and SR-BI-mediated selective uptake (p < 0.01), two key steps in RCT. Consistently, also the in vivo capacity of ESRD-HDL to promote RCT when infused into wildtype mice was significantly impaired (p < 0.01). In vitro oxidation of HDL from healthy controls with hypochloric acid was able to fully mimic the impaired biological activities of ESRD-HDL. In conclusion, we demonstrate that HDL from ESRD patients is dysfunctional in key steps as well as overall RCT, likely due to oxidative modification.