Functional rescue of mutant ABCA1 proteins by sodium 4-phenylbutyrate
Functional rescue of mutant ABCA1 proteins by sodium 4-phenylbutyrate
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DOI：
10.1194/jlr.m027193
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发表时间：
2013-01-01
影响因子：
6.5
通讯作者：
McCormick, Sally P. A.
中科院分区：
文献类型：
--
作者：
Sorrenson, Brie;Suetani, Rachel J.;McCormick, Sally P. A.
ATP结合盒转运蛋白A1（ABCA1）的突变是导致HDL胆固醇（HDL-C）降低的主要原因，这意味着心血管疾病（CVD）的风险增加。许多ABCA1突变体显示出质膜定位受损。本研究的目的是研究化学伴侣4-苯基丁酸钠（4-PBA）是否可以改善ABCA 1突变体的细胞定位和功能。用4-PBA处理HEK293细胞中表达的9种不同ABCA 1突变体（p.A594T、p.I659V、p.R1068H、p.T1512M、p.Y1767D、p.N1800H、p.R2004K、p.A2028V、p.Q2239N），这些突变体显示出不同程度的质膜错误定位和对胆固醇流出的离散影响。治疗恢复定位到质膜和增加胆固醇流出功能的大多数突变体。用4-PBA处理也增加了所有转染细胞系中ABCA 1蛋白的表达。在从表达两种ABCA 1突变体（p.R1068H和p.N1800H）的低HDL-C受试者获得的成纤维细胞中，4-PBA增加胆固醇流出，而ABCA 1表达无任何增加。我们的研究是第一个调查的化学伴侣，4-PBA对ABCA1的影响，并表明，它是能够恢复质膜定位和增强胆固醇流出功能的突变ABCA1s在体外和离体。这些结果表明，4-PBA可能值得进一步研究，作为一种潜在的治疗增加胆固醇流出和HDL-C水平。Sorrenson，B.，R. J. Suetani，M. J. A.威廉姆斯，V.M.放大图片作者：比克利.乔治，G. t. Jones和S. p. A.麦考密克4-苯基丁酸钠对突变ABCA 1蛋白的功能性拯救。J. Lipid Res. 2013. 54：55 - 62。
Mutations in the ATP-binding cassette transporter A1 (ABCA1) are a major cause of decreased HDL cholesterol (HDL-C), which infers an increased risk of cardiovascular disease (CVD). Many ABCA1 mutants show impaired localization to the plasma membrane. The aim of this study was to investigate whether the chemical chaperone, sodium 4-phenylbutyrate (4-PBA) could improve cellular localization and function of ABCA1 mutants. Nine different ABCA1 mutants (p.A594T, p.I659V, p.R1068H, p.T1512M, p.Y1767D, p.N1800H, p.R2004K, p.A2028V, p.Q2239N) expressed in HEK293 cells, displaying different degrees of mislocalization to the plasma membrane and discrete impacts on cholesterol efflux, were subject to treatment with 4-PBA. Treatment restored localization to the plasma membrane and increased cholesterol efflux function for the majority of mutants. Treatment with 4-PBA also increased ABCA1 protein expression in all transfected cell lines. In fibroblast cells obtained from low HDL-C subjects expressing two of the ABCA1 mutants (p.R1068H and p.N1800H), 4-PBA increased cholesterol efflux without any increase in ABCA1 expression. Our study is the first to investigate the effect of the chemical chaperone, 4-PBA on ABCA1 and shows that it is capable of restoring plasma membrane localization and enhancing the cholesterol efflux function of mutant ABCA1s both in vitro and ex vivo. These results suggest 4-PBA may warrant further investigation as a potential therapy for increasing cholesterol efflux and HDL-C levels. Sorrenson, B., R. J. Suetani, M. J. A. Williams, V. M. Bickley, Peter M. George, G. T. Jones, and S. P. A. McCormick. Functional rescue of mutant ABCA1 proteins by sodium 4-phenylbutyrate. J. Lipid Res. 2013. 54: 55-62.