ABCA8 Regulates Cholesterol Efflux and High-Density Lipoprotein Cholesterol Levels

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

来源：Arteriosclerosis, Thrombosis, and Vascular Biology, 2017, 37(11): 2147-+.

DOI：10.1161/ATVBAHA.117.309574

• atherosclerosis
• ATP-binding cassette transporters
• cholesterol, HDL
• reverse cholesterol transport

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.

• 出版日期2017