TRAK2, a novel regulator of ABCA1 expression, cholesterol efflux and HDL biogenesis
dc.contributor.author | Lake, N. | |
dc.contributor.author | Taylor, R. | |
dc.contributor.author | Trahair, H. | |
dc.contributor.author | Harikrishnan, K. | |
dc.contributor.author | Curran, J. | |
dc.contributor.author | Almeida, M. | |
dc.contributor.author | Kulkarni, H. | |
dc.contributor.author | Mukhamedova, N. | |
dc.contributor.author | Hoang, A. | |
dc.contributor.author | Low, H. | |
dc.contributor.author | Murphy, A. | |
dc.contributor.author | Johnson, M. | |
dc.contributor.author | Dyer, T. | |
dc.contributor.author | Mahaney, M. | |
dc.contributor.author | Göring, H. | |
dc.contributor.author | Moses, Eric | |
dc.contributor.author | Sviridov, D. | |
dc.contributor.author | Blangero, J. | |
dc.contributor.author | Jowett, J. | |
dc.contributor.author | Bozaoglu, K. | |
dc.date.accessioned | 2018-02-06T06:17:02Z | |
dc.date.available | 2018-02-06T06:17:02Z | |
dc.date.created | 2018-02-06T05:49:55Z | |
dc.date.issued | 2017 | |
dc.identifier.citation | Lake, N. and Taylor, R. and Trahair, H. and Harikrishnan, K. and Curran, J. and Almeida, M. and Kulkarni, H. et al. 2017. TRAK2, a novel regulator of ABCA1 expression, cholesterol efflux and HDL biogenesis. European Heart Journal. 38 (48): pp. 3579-3587. | |
dc.identifier.uri | http://hdl.handle.net/20.500.11937/63381 | |
dc.identifier.doi | 10.1093/eurheartj/ehx315 | |
dc.description.abstract |
© The Author 2017. Aims The recent failures of HDL-raising therapies have underscored our incomplete understanding of HDL biology. Therefore there is an urgent need to comprehensively investigate HDL metabolism to enable the development of effective HDL-centric therapies. To identify novel regulators of HDL metabolism, we performed a joint analysis of human genetic, transcriptomic, and plasma HDL-cholesterol (HDL-C) concentration data and identified a novel association between trafficking protein, kinesin binding 2 (TRAK2) and HDL-C concentration. Here we characterize the molecular basis of the novel association between TRAK2 and HDL-cholesterol concentration. Methods and results Analysis of lymphocyte transcriptomic data together with plasma HDL from the San Antonio Family Heart Study (n = 1240) revealed a significant negative correlation between TRAK2 mRNA levels and HDL-C concentration, HDL particle diameter and HDL subspecies heterogeneity. TRAK2 siRNA-mediated knockdown significantly increased cholesterol efflux to apolipoprotein A-I and isolated HDL from human macrophage (THP-1) and liver (HepG2) cells by increasing the mRNA and protein expression of the cholesterol transporter ATP-binding cassette, sub-family A member 1 (ABCA1). The effect of TRAK2 knockdown on cholesterol efflux was abolished in the absence of ABCA1, indicating that TRAK2 functions in an ABCA1-dependent efflux pathway. TRAK2 knockdown significantly increased liver X receptor (LXR) binding at the ABCA1 promoter, establishing TRAK2 as a regulator of LXR-mediated transcription of ABCA1. Conclusion We show, for the first time, that TRAK2 is a novel regulator of LXR-mediated ABCA1 expression, cholesterol efflux, and HDL biogenesis. TRAK2 may therefore be an important target in the development of antiatherosclerotic therapies. | |
dc.publisher | Oxford University Press | |
dc.title | TRAK2, a novel regulator of ABCA1 expression, cholesterol efflux and HDL biogenesis | |
dc.type | Journal Article | |
dcterms.source.volume | 38 | |
dcterms.source.number | 48 | |
dcterms.source.startPage | 3579 | |
dcterms.source.endPage | 3587 | |
dcterms.source.issn | 0195-668X | |
dcterms.source.title | European Heart Journal | |
curtin.department | School of Pharmacy and Biomedical Sciences | |
curtin.accessStatus | Fulltext not available |
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