HDL and its primary receptor, scavenger receptor BI (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), that 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 wild-type or R174C-SR-BI. Although R174C-SR-BI was expressed at levels comparable to the wild-type 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.

中文翻译：

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清道夫受体 BI (R174C) 的人类变体表现出胆固醇转运功能受损。


HDL 及其主要受体清道夫受体 BI (SR-BI) 共同作用，促进过量血浆胆固醇的清除，从而预防动脉粥样硬化。 SR-BI 的人类变异体已在高 HDL 胆固醇水平的患者中被发现，并且至少一种变异体与心血管疾病有关。因此，虽然高密度脂蛋白胆固醇通常被认为是有益的，但过高水平的高密度脂蛋白胆固醇可能是由于 SR-BI 的胆固醇清除受损而导致的，并会增加心血管风险。在这项研究中，我们表征了 SR-BI 的一种罕见人类变体的功能，该变体导致精氨酸 174 被半胱氨酸 (R174C) 取代，这种情况之前在具有高 HDL 胆固醇水平的杂合个体中被发现。我们假设 R174C-SR-BI 变体损害了胆固醇转运功能，并在用全长野生型或 R174C-SR-BI 瞬时转染后的 COS-7 细胞中进行了评估。尽管R174C-SR-BI的表达水平与野生型受体相当，但在R174C-SR-BI存在的情况下，HDL结合、胆固醇十六烷基醚摄取、游离胆固醇流出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。如果可翻译，这种人类变异可能会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。