Human variant of scavenger receptor BI (R174C) exhibits impaired cholesterol transport functions.
Human variant of scavenger receptor BI (R174C) exhibits impaired cholesterol transport functions.
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DOI：
10.1016/j.jlr.2021.100045
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发表时间：
2021
影响因子：
6.5
通讯作者：
Sahoo D
中科院分区：
文献类型：
--
作者：
May SC;Dron JS;Hegele RA;Sahoo D
高密度脂蛋白及其主要受体，清道夫受体B类I型（SR-BI），共同促进清除多余的血浆胆固醇，从而防止动脉粥样硬化。在高密度脂蛋白胆固醇水平高的患者中发现了SR-BI的人类变体，并且至少有一种变体与心血管疾病有关。因此，虽然通常被认为是有益的，但高水平的高密度脂蛋白胆固醇可能会导致SR-BI对胆固醇的清除受损，并增加心血管风险。在这项研究中，我们描述了一种罕见的人类SR-BI变异的功能，导致精氨酸-174被半胱氨酸（R174C）取代，这是之前在一个高水平hdl -胆固醇的杂合个体中发现的。我们假设R174C-SR-BI变体损害了胆固醇运输功能，这是在用全长WT或R174C-SR-BI短暂转染COS-7细胞后评估的。尽管R174C-SR-BI的表达水平与WT受体相当，但在R174C-SR-BI的存在下，HDL结合、胆固醇十六烷基醚摄取、游离胆固醇外排和膜胆固醇调节被破坏。我们进一步研究了盐桥作为R174C-SR-BI功能障碍的潜在机制的作用。如果可以翻译，这种人类变异可能导致血浆高密度脂蛋白胆固醇水平升高，胆固醇清除受损，并增加心血管疾病的风险。
HDL and its primary receptor, scavenger receptor class B type I (SR-BI), work together to promote the clearance of excess plasma cholesterol, thereby protecting against atherosclerosis. Human variants of SR-BI have been identified in patients with high HDL-cholesterol levels, and at least one variant has been linked to cardiovascular disease. Therefore, while often regarded as beneficial, very high levels of HDL-cholesterol may result from impaired cholesterol clearance through SR-BI and contribute to cardiovascular risk. In this study, we characterized the function of a rare human variant of SR-BI, resulting in the substitution of arginine-174 with cysteine (R174C), which was previously identified in a heterozygous individual with high levels of HDL-cholesterol. We hypothesized that the R174C-SR-BI variant has impaired cholesterol transport functions, which were assessed in COS-7 cells after transient transfection with full-length WT or R174C-SR-BI. Although R174C-SR-BI was expressed at levels comparable to the WT receptor, HDL binding, cholesteryl hexadecyl ether uptake, free cholesterol efflux, and modulation of membrane cholesterol were disrupted in the presence of R174C-SR-BI. We further examined the role of salt bridges as a potential mechanism for R174C-SR-BI dysfunction. If translatable, this human variant could lead to increased plasma HDL-cholesterol levels, impaired cholesterol clearance, and increased cardiovascular disease risk.
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