期刊
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
卷 37, 期 11, 页码 2147-+出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.117.309574
关键词
atherosclerosis; ATP-binding cassette transporters; cholesterol, HDL; reverse cholesterol transport
资金
- Xenon Pharmaceuticals (Burnaby, BC, Canada)
- Merck (Rahway, New Jersey)
- Agency for Science, Technology and Research (A*STAR, Singapore)
- National University of Singapore
- CardioVascular Research Initiative (Genius) [CVON2011-19]
- European Union [FP7-305707, FP7-603091-2]
- Austrian Science Fund [I 2738-B26]
- Netherlands Organisation for Scientific Research (Nederlandse Organisatie voor Wetenschappelijk Onderzoek) [016.156.445]
- National University of Singapore via Life Sciences Institute (LSI)
- National Research Foundation [NRFI2015-05]
- BMRC-SERC from Agency for Science, Technology and Research (A*STAR) [BMRC-SERC 112 148 0006]
- Austrian Science Fund (FWF) [I2738] Funding Source: Austrian Science Fund (FWF)
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.
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