ABCA8 Regulates Cholesterol Efflux and High-Density Lipoprotein Cholesterol Levels

Abstract

© 2017 American Heart Association, Inc. 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 identifed 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 identifed, 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 frst-degree family controls (0.86?0.34 versus 1.17?0.26 mmol/L; P=0.005). HDLc levels were signifcantly 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 signifcant increases in plasma HDLc and the frst steps of macrophage-to-feces reverse cholesterol transport. Overexpression of wild-type but not mutant ABCA8 resulted in a signifcant 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.