TY - JOUR
T1 - ABCA8 Regulates Cholesterol Efflux and High-Density Lipoprotein Cholesterol Levels
AU - Trigueros-Motos, Laia
AU - van Capelleveen, Julian C.
AU - Torta, Federico
AU - Castaño, David
AU - Zhang, Lin-Hua
AU - Chai, Ee Chu
AU - Kang, Martin
AU - Dimova, Lidiya G.
AU - Schimmel, Alinda W. M.
AU - Tietjen, Ian
AU - Radomski, Chris
AU - Tan, Liang Juin
AU - Thiam, Chung Hwee
AU - Narayanaswamy, Pradeep
AU - Wu, Daniel Heqing
AU - Dorninger, Fabian
AU - Yakala, Gopala Krishna
AU - Barhdadi, Amina
AU - Angeli, Veronique
AU - Dubé, Marie-Pierre
AU - Berger, Johannes
AU - Dallinga-Thie, Geesje M.
AU - Tietge, Uwe J. F.
AU - Wenk, Markus R.
AU - Hayden, Michael R.
AU - Hovingh, G. Kees
AU - Singaraja, Roshni R.
PY - 2017
Y1 - 2017
N2 - 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
AB - 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
U2 - https://doi.org/10.1161/ATVBAHA.117.309574
DO - https://doi.org/10.1161/ATVBAHA.117.309574
M3 - Article
C2 - 28882873
SN - 1079-5642
VL - 37
SP - 2147
EP - 2155
JO - Arteriosclerosis, Thrombosis, and Vascular Biology
JF - Arteriosclerosis, Thrombosis, and Vascular Biology
IS - 11
ER -