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Eur Heart J. 2017 Dec 21;38(48):3579-3587. doi: 10.1093/eurheartj/ehx315.

TRAK2, a novel regulator of ABCA1 expression, cholesterol efflux and HDL biogenesis.

Author information

1
Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia.
2
Murdoch Children's Research Institute, 50 Flemington Road, Parkville, VIC 3052, Australia.
3
Department of Pathology, University of Melbourne, Grattan Street, Parkville, VIC 3010, Australia.
4
South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, One West University Blvd. Brownsville, Texas 78520, USA.
5
University of Western Australia, 35 Stirling Hwy, Crawley, WA 6009, Australia.
6
Curtin University, Kent St, Bentley, WA 6102, Australia.
7
Department of Paediatrics, University of Melbourne, 50 Flemington Road, Parkville,VIC 3052, Australia.

Abstract

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 anti-atherosclerotic therapies.

KEYWORDS:

ABCA1 ; Atherosclerosis ; Cholesterol ; Genetics ; HDL ; TRAK2

PMID:
28655204
PMCID:
PMC6251650
[Available on 2018-12-21]
DOI:
10.1093/eurheartj/ehx315

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