Functional rescue of mutant ABCA1 proteins by sodium 4-phenylbutyrate

Rachel J. Suetani,Sally P.A. McCormick,Vivienne M. Bickley,Brie Sorrenson,Peter M. George,Michael J.A. Williams,Gregory T. Jones

doi:10.1194/jlr.m027193

Rachel J. Suetani, Sally P.A. McCormick + Show 5 more

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https://doi.org/10.1194/jlr.m027193

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Abstract

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.

Highlights

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)
4-PBA treatment was applied to the six uncharacterized ABCA1 mutants as well as to three mutants that we have previously shown to have reduced cholesterol efflux function, p.R1068H [19], p.T1512M [20], and p.N1800H (20, Fig. 1)
The ABCA1 protein is very intolerant to structural change and many ABCA1 mutants exhibit misfolding and intracellular retention [1, 3, 4], leading to a lack of functional protein at the plasma membrane and associated low HDL-C levels

Summary

Introduction

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). Treatment restored localization to the plasma membrane and increased cholesterol efflux function for the majority of mutants. 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.

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