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

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. 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. 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.

Citation

Nicole J Lake, Rachael L Taylor, Hugh Trahair, K N Harikrishnan, Joanne E Curran, Marcio Almeida, Hemant Kulkarni, Nigora Mukhamedova, Anh Hoang, Hann Low, Andrew J Murphy, Matthew P Johnson, Thomas D Dyer, Michael C Mahaney, Harald H H Göring, Eric K Moses, Dmitri Sviridov, John Blangero, Jeremy B M Jowett, Kiymet Bozaoglu. TRAK2, a novel regulator of ABCA1 expression, cholesterol efflux and HDL biogenesis. European heart journal. 2017 Jun 26

PMID: 28655204

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