Apolipoprotein A-I (ApoA-I) of high-density lipoprotein (HDL) is essential for the transportation of cholesterol between peripheral tissues and the liver. However, specific mutations in Apolipoprotein A-I (ApoA-I) of high-density lipoprotein (HDL) are responsible for a late-onset systemic amyloidosis, the pathological accumulation of protein fibrils in tissues and organs. Carriers of these mutations do not exhibit increased cardiovascular disease risk despite displaying reduced levels of ApoA-I/ HDL-cholesterol. To explain this paradox, we show that the HDL particle profile of patients carrying either L75P or L174S ApoA-I amyloidogenic variants a higher relative abundance of the 8.4 nm vs 9.6 nm particles, and that serum from patients, as well as reconstituted 8.4 and 9.6 nm HDL particles (rHDL), possess increased capacity to catalyze cholesterol efflux from macrophages. Synchrotron radiation circular dichroism and hydrogen-deuterium exchange revealed that the variants in 8.4 nm rHDL have altered secondary structure composition and display a more flexible binding to lipids compared to their native counterpart. The reduced HDL-cholesterol levels of patients carrying ApoA-I amyloidogenic variants are thus balanced by higher proportion of small, dense HDL particles and better cholesterol efflux due to altered, region-specific protein structure dynamics.

中文翻译：

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小 HDL 中 ApoA-I 淀粉样变体的结构动力学增加了它们介导胆固醇流出的能力。


高密度脂蛋白 (HDL) 的载脂蛋白 AI (ApoA-I) 对于胆固醇在外周组织和肝脏之间的运输至关重要。然而，高密度脂蛋白 (HDL) 载脂蛋白 AI (ApoA-I) 的特定突变导致迟发性系统性淀粉样变性，即组织和器官中蛋白原纤维的病理性积累。尽管 ApoA-I/HDL-胆固醇水平降低，但这些突变的携带者并未表现出心血管疾病风险增加。为了解释这一悖论，我们显示携带 L75P 或 L174S ApoA-I 淀粉样变体的患者的 HDL 颗粒特征，8.4 nm 颗粒相对于 9.6 nm 颗粒的相对丰度更高，并且来自患者的血清以及重构的 8.4 和 9.6 nm HDL 颗粒（rHDL）具有更强的催化巨噬细胞胆固醇流出的能力。同步辐射圆二色性和氢-氘交换表明，8.4 nm rHDL 中的变体改变了二级结构组成，并且与天然对应物相比，表现出更灵活的脂质结合。因此，携带 ApoA-I 淀粉样变体的患者 HDL 胆固醇水平降低，通过较高比例的小而致密的 HDL 颗粒和由于区域特异性蛋白质结构动力学改变而更好的胆固醇流出来平衡。