A loss-of-function variant in OSBPL1A predisposes to low plasma HDL cholesterol levels and impaired cholesterol efflux capacity
A loss-of-function variant in OSBPL1A predisposes to low plasma HDL cholesterol levels and impaired cholesterol efflux capacity
复制标题
DOI：
10.1016/j.atherosclerosis.2016.04.005
复制
发表时间：
2016-06-01
期刊：
影响因子：
5.3
通讯作者：
Olkkonen, Vesa M.
中科院分区：
文献类型：
--
作者：
Motazacker, Mahdi M.;Pirhonen, Juho;Olkkonen, Vesa M.
背景与目的：在普通人群中高密度脂蛋白胆固醇(HDLc)低于1百分位数的受试者中，我们发现了一个OSBPL1Ap.C39X杂合体，其编码一个与低HDLC共分离的短截短蛋白片段。方法：我们研究了携带者和非携带者的HDL组分和功能，并研究了突变蛋白在培养肝细胞中的性质。结果：携带者血浆HDLC和载脂蛋白(Apo)A-I低于非携带者，而其他被分析的血浆成分或高密度脂蛋白参数没有差异。携带者的血清作为胆固醇外流受体的能力降低(p<；0.01)，而他们分离的高密度脂蛋白的胆固醇受体能力正常。来自P.C39X载体的成纤维细胞显示胆固醇外流到无脂apoA-I的减少，但不能外流成熟的高密度脂蛋白颗粒，这表明ABCA1介导的外流途径存在特殊缺陷。在肝细胞中，GFP-OSBPL1A部分共定位于含有荧光apoA-I的内体中，提示OSBPL1A可能调节apoA-I的细胞内处理。GFP-OSBPL1A-39x突变蛋白保留在胞浆中，不能与Rab7相互作用，Rab7通常将OSBPL1A招募到晚期内切/溶酶体内，表明该突变代表功能丧失。结论：本工作首次表征了人类OSBPL1A突变。我们的观察提供了证据，OSBPL1A的家族性功能丧失突变会影响胆固醇反向运输过程的第一步，并与低高密度脂蛋白-C表型相关。这表明OSBPL基因的罕见突变可能与血脂异常有关。(C)2016爱思唯尔爱尔兰有限公司。保留所有权利。
Background and aims: Among subjects with high-density-lipoprotein cholesterol (HDL-C) below the 1st percentile in the general population, we identified a heterozygous variant OSBPL1A p.C39X encoding a short truncated protein fragment that co-segregated with low plasma HDL-C.Methods: We investigated the composition and function of HDL from the carriers and non-carriers and studied the properties of the mutant protein in cultured hepatocytes.Results: Plasma HDL-C and apolipoprotein (apo) A-I were lower in carriers versus non-carriers, whereas the other analyzed plasma components or HDL parameters did not differ. Sera of the carriers displayed a reduced capacity to act as cholesterol efflux acceptors (p < 0.01), whereas the cholesterol acceptor capacity of their isolated HDL was normal. Fibroblasts from a p.C39X carrier showed reduced cholesterol efflux to lipid-free apoA-I but not to mature HDL particles, suggesting a specific defect in ABCA1-mediated efflux pathway. In hepatic cells, GFP-OSBPL1A partially co-localized in endosomes containing fluorescent apoA-I, suggesting that OSBPL1A may regulate the intracellular handling of apoA-I. The GFP-OSBPL1A-39X mutant protein remained in the cytosol and failed to interact with Rab7, which normally recruits OSBPL1A to late endosomes/lysosomes, suggesting that this mutation represents a loss-of-function.Conclusions: The present work represents the first characterization of a human OSBPL1A mutation. Our observations provide evidence that a familial loss-of-function mutation in OSBPL1A affects the first step of the reverse cholesterol transport process and associates with a low HDL-C phenotype. This suggests that rare mutations in OSBPL genes may contribute to dyslipidemias. (C) 2016 Elsevier Ireland Ltd. All rights reserved.