ApoA-I cleaved by transthyretin has reduced ability to promote cholesterol efflux and increased amyloidogenicity
ApoA-I cleaved by transthyretin has reduced ability to promote cholesterol efflux and increased amyloidogenicity
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DOI：
10.1194/jlr.m700158-jlr200
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发表时间：
2007-11-01
影响因子：
6.5
通讯作者：
Sousa, Monica Mendes
中科院分区：
文献类型：
--
作者：
Liz, Marcia Almeida;Gomes, Claudio M.;Sousa, Monica Mendes
一部分血浆甲状腺素运载蛋白（TTR）通过与载脂蛋白A-I（apoA-I）结合在HDL中循环。此外，TTR能够切割无脂质的apoA-I的C末端。在这项研究中，我们解决了TTR在脂蛋白代谢和apoA-I淀粉样纤维形成中apoA-I裂解的相关性。我们确定TTR也可以切割脂化的apoA-I，其中切割在脂质贫乏的前β-HDL亚群中更有效。TTR裂解后，盘状HDL颗粒显示出降低的促进胆固醇从胆固醇负载的THP-1巨噬细胞流出的能力。在类似的试验中，与来自TTR敲除小鼠的类似颗粒相比，来自在TTR敲除背景下表达人TTR的小鼠的含TTR的HDL进行反向胆固醇转运的能力降低，加强了TTR切割降低apoA-I促进胆固醇流出的能力的观点。由于N-末端apoA-I片段组成的淀粉样蛋白沉积物在动脉粥样硬化内膜中很常见，我们评估了TTR裂解对apoA-I聚集和纤维生长的影响。我们确定TTR切割的apoA-I具有形成聚集颗粒的高倾向，并且它形成原纤维的速度比全长apoA-I快，如通过电子显微镜所评估的。我们的研究结果表明，TTR切割apoA-I可能会影响HDL生物学和动脉粥样硬化的发展，减少胆固醇流出和增加apoA-I淀粉样蛋白的潜力。
A fraction of plasma transthyretin ( TTR) circulates in HDL through binding to apolipoprotein A-I ( apoA-I). Moreover, TTR is able to cleave the C terminus of lipid-free apoA-I. In this study, we addressed the relevance of apoA-I cleavage by TTR in lipoprotein metabolism and in the formation of apoA-I amyloid fibrils. We determined that TTR may also cleave lipidated apoA-I, with cleavage being more effective in the lipid-poor pre beta-HDL subpopulation. Upon TTR cleavage, discoidal HDL particles displayed a reduced capacity to promote cholesterol efflux from cholesterol-loaded THP-1 macrophages. In similar assays, TTR-containing HDL from mice expressing human TTR in a TTR knockout background had a decreased ability to perform reverse cholesterol transport compared with similar particles from TTR knockout mice, reinforcing the notion that cleavage by TTR reduces the ability of apoA-I to promote cholesterol efflux. As amyloid deposits composed of N-terminal apoA-I fragments are common in the atherosclerotic intima, we assessed the impact of TTR cleavage on apoA-I aggregation and fibrillar growth. We determined that TTR-cleaved apoA-I has a high propensity to form aggregated particles and that it formed fibrils faster than full-length apoA-I, as assessed by electron microscopy. Our results show that apoA-I cleavage by TTR may affect HDL biology and the development of atherosclerosis by reducing cholesterol efflux and increasing the apoA-I amyloidogenic potential.