ABCA8 Regulates Cholesterol Efflux and High-Density Lipoprotein Cholesterol Levels

Arterioscler Thromb Vasc Biol. 2017 Nov;37(11):2147-2155. doi: 10.1161/ATVBAHA.117.309574.

Laia Trigueros-Motos ¹, Julian C van Capelleveen ¹, Federico Torta ¹, David Castaño ¹, Lin-Hua Zhang ¹, Ee Chu Chai ¹, Martin Kang ¹, Lidiya G Dimova ¹, Alinda W M Schimmel ¹, Ian Tietjen ¹, Chris Radomski ¹, Liang Juin Tan ¹, Chung Hwee Thiam ¹, Pradeep Narayanaswamy ¹, Daniel Heqing Wu ¹, Fabian Dorninger ¹, Gopala Krishna Yakala ¹, Amina Barhdadi ¹, Veronique Angeli ¹, Marie-Pierre Dubé ¹, Johannes Berger ¹, Geesje M Dallinga-Thie ¹, Uwe J F Tietge ¹, Markus R Wenk ¹, Michael R Hayden ¹, G Kees Hovingh ¹, Roshni R Singaraja ²

Affiliations

1 From the Translational Laboratory in Genetic Medicine, A*STAR Institute, and Yong Loo Lin School of Medicine, National University of Singapore (L.T.-M., D.C., E.C.C., L.J.T., D.H.W., G.K.Y., M.R.H., R.R.S.); Departments of Vascular Medicine and Experimental Vascular Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands (J.C.v.C., A.W.M.S., G.M.D.-T., G.K.H.); Faculty of Health Sciences, Simon Fraser University, Canada (I.T.); Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (F.T., P.N., M.R.W.); Centre for Molecular Medicine and Therapeutics and Child and Family Research Institute, University of British Columbia, Canada (L.-H.Z., M.K., M.R.H.); Department of Pediatrics, University Medical Center Groningen, University of Groningen, The Netherlands (L.G.D., U.J.F.T.); Xenon Pharmaceuticals, Burnaby, Canada (I.T., C.R.); Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore (C.H.T., V.A.); Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Austria (F.D., J.B.); Beaulieu-Saucier Université de Montréal Pharmacogenomics Centre, Canada (A.B., M.-P.D.); Montréal Heart Institute Research Centre, Canada (A.B., M.-P.D.); and Université de Montréal, Canada (A.B., M.-P.D.).
2 From the Translational Laboratory in Genetic Medicine, A*STAR Institute, and Yong Loo Lin School of Medicine, National University of Singapore (L.T.-M., D.C., E.C.C., L.J.T., D.H.W., G.K.Y., M.R.H., R.R.S.); Departments of Vascular Medicine and Experimental Vascular Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands (J.C.v.C., A.W.M.S., G.M.D.-T., G.K.H.); Faculty of Health Sciences, Simon Fraser University, Canada (I.T.); Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (F.T., P.N., M.R.W.); Centre for Molecular Medicine and Therapeutics and Child and Family Research Institute, University of British Columbia, Canada (L.-H.Z., M.K., M.R.H.); Department of Pediatrics, University Medical Center Groningen, University of Groningen, The Netherlands (L.G.D., U.J.F.T.); Xenon Pharmaceuticals, Burnaby, Canada (I.T., C.R.); Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore (C.H.T., V.A.); Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Austria (F.D., J.B.); Beaulieu-Saucier Université de Montréal Pharmacogenomics Centre, Canada (A.B., M.-P.D.); Montréal Heart Institute Research Centre, Canada (A.B., M.-P.D.); and Université de Montréal, Canada (A.B., M.-P.D.). rsingaraja@tlgm.a-star.edu.sg.

PMID: 28882873 DOI: 10.1161/ATVBAHA.117.309574

Abstract

Objective: High-density lipoproteins (HDL) are considered to protect against atherosclerosis in part by facilitating the removal of Cholesterol from peripheral tissues. However, factors regulating lipid efflux are incompletely understood. We previously identified a variant in adenosine triphosphate-binding cassette transporter A8 (ABCA8) in an individual with low HDL Cholesterol (HDLc). Here, we investigate the role of ABCA8 in Cholesterol efflux and in regulating HDLc levels.

Approach and results: We sequenced ABCA8 in individuals with low and high HDLc and identified, exclusively in low HDLc probands, 3 predicted deleterious heterozygous ABCA8 mutations (p.Pro609Arg [P609R], IVS17-2 A>G and p.Thr741Stop [T741X]). HDLc levels were lower in heterozygous mutation carriers compared with first-degree family controls (0.86±0.34 versus 1.17±0.26 mmol/L; P=0.005). HDLc levels were significantly decreased by 29% (P=0.01) in Abca8b^-/- mice on a high-cholesterol diet compared with wild-type mice, whereas hepatic overexpression of human ABCA8 in mice resulted in significant increases in plasma HDLc and the first steps of macrophage-to-feces reverse Cholesterol transport. Overexpression of wild-type but not mutant ABCA8 resulted in a significant increase (1.8-fold; P=0.01) of Cholesterol efflux to Apolipoprotein AI in vitro. ABCA8 colocalizes and interacts with adenosine triphosphate-binding cassette transporter A1 and further potentiates adenosine triphosphate-binding cassette transporter A1-mediated Cholesterol efflux.

Conclusions: ABCA8 facilitates Cholesterol efflux and modulates HDLc levels in humans and mice.

Keywords

ATP-binding cassette transporters; atherosclerosis; cholesterol, HDL; reverse cholesterol transport.

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