ABCA8 Regulates Cholesterol Efflux and High-Density Lipoprotein Cholesterol Levels.

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.

• Authors: Laia Trigueros-Motos, Julian C van Capelleveen, Federico Torta, David Castaño, Lin-Hua Zhang, Ee Chu Chai, Martin Kang, Lidiya G Dimova, Alinda W M Schimmel, Ian Tietjen, Chris Radomski, Liang Juin Tan, Chung Hwee Thiam, Pradeep Narayanaswamy, Daniel Heqing Wu, Fabian Dorninger, Gopala Krishna Yakala, Amina Barhdadi, Veronique Angeli, Marie-Pierre Dubé, Johannes Berger, Geesje M Dallinga-Thie, Uwe J F Tietge, Markus R Wenk, Michael R Hayden, G Kees Hovingh, Roshni R Singaraja
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 37 Issue 11 Pg. 2147-2155 (11 2017) ISSN: 1524-4636 [Electronic] United States
• PMID: 28882873 (Publication Type: Journal Article)
• Copyright: © 2017 American Heart Association, Inc.

Chemical References

• ABCA8 protein, human
• APOA1 protein, human
• APOB protein, human
• ATP-Binding Cassette Transporters
• Abca8b protein, mouse
• Apolipoprotein A-I
• Apolipoprotein B-100
• Biomarkers
• Cholesterol, Dietary
• Cholesterol, HDL

Topics

• ATP-Binding Cassette Transporters (deficiency, genetics, metabolism)
• Adult
• Aged
• Animals
• Apolipoprotein A-I (blood)
• Apolipoprotein B-100 (blood)
• Biological Transport
• Biomarkers (blood)
• COS Cells
• Case-Control Studies
• Chlorocebus aethiops
• Cholesterol, Dietary (blood)
• Cholesterol, HDL (blood)
• DNA Mutational Analysis
• Diet, High-Fat
• Feces (chemistry)
• Female
• HEK293 Cells
• Heredity
• Heterozygote
• Humans
• Liver (metabolism)
• Macrophages (metabolism)
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Middle Aged
• Mutation
• Pedigree
• Phenotype
• Transfection