Skip to main content

Graphical Abstract

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.

Introduction

Cardiovascular disease is the leading cause of death worldwide.1 Prospective epidemiological studies have established a robust inverse correlation between high-density lipoprotein cholesterol (HDLc) levels and risk for cardiovascular disease.2 However, simply raising HDLc levels may be insufficient to protect against coronary artery disease.3,4 These seemingly counterintuitive findings underscore the crucial need for greater understanding of HDL biology.
Atherosclerosis, characterized by the accumulation of lipids and cholesterol-filled macrophages in the arterial wall,5 is the pathological process underlying cardiovascular disease. Prevention of intracellular cholesterol accumulation through decreasing uptake and/or increasing efflux of cholesterol to extracellular lipoproteins is necessary to maintain macrophage lipid homeostasis.6 Cholesterol efflux is an early step in the reverse cholesterol transport (RCT) pathway, a process by which HDL particles transport cholesterol from extrahepatic tissues to the liver, for subsequent excretion in bile.7 Indeed, this aspect of HDL functionality is strongly and inversely correlated with coronary heart disease in many, but not all studies.810 Two major transport proteins have been shown to facilitate cholesterol efflux and play a role in RCT, the adenosine triphosphate–binding cassette transporters A1 (ABCA1) and G1.11 ABCA1 plays a critical role as a transporter of intracellular free cholesterol and phospholipids to the extracellular acceptor apolipoprotein AI (ApoA-I), to form nascent HDL.12 Mature HDL particles act as acceptors for adenosine triphosphate–binding cassette transporters G1–mediated cholesterol efflux.11
Family and twin studies estimate that HDLc has a heritability of between 40% and 60%, and a substantial portion of HDLc heritability remains to be elucidated.13 Recent genome-wide association studies have identified numerous genetic loci that associate with significant changes in plasma HDLc levels across large populations.13 However, few of these loci have been functionally investigated. One of these variants, rs4148008 in ABCA8 was reported to be significantly associated with an average 0.42 mg/dL decrease in HDLc levels.14 The rs4148008 variant is localized in intron 30 of ABCA8, and has a global minor allele frequency of 0.42 in dbSNP and 0.29 in Hapmap central Europeans. In support of this association, we previously identified a single proband with low HDLc who carries a predicted loss of function mutation, p.Thr741Stop, in ABCA8.15 Although the function of ABCA8 remained to be elucidated, it belongs to the ABC transporter family, suggesting it might play a role in HDL metabolism and cholesterol efflux in a similar fashion as the canonical cholesterol efflux proteins ABCA1 and adenosine triphosphate–binding cassette transporters G1. Here, we identified ABCA8 as a new protein involved in cholesterol efflux and characterized its role in RCT and in modulating HDLc levels.

Materials and Methods

Materials and Methods are available in the online-only Data Supplement.

Results

ABCA8 Mutations Are Found in Probands With Low HDLc

To determine if mutations in ABCA8 could result in low plasma HDLc levels, we sequenced ABCA8 in 80 probands with HDLc<10th percentile in whom mutations in LCAT, APOA1, and ABCA1 were previously excluded.16 As controls, 120 probands with HDLc≥90th percentile were sequenced. Sequencing of the 39 exons and exon–intron boundaries of ABCA8 resulted in the identification of 2 probands exclusively in the low HDLc cohort with potential mutations. These variants are p.Pro609Arg (P609R, rs144777539, chromosome 17:66914289 G>C) and c.IVS17-2 A>G (Chromosome 17:66899693, genome build 37.3) (Figure 1A). We also previously identified an individual with HDLc≤5th percentile, harboring a nonsense mutation, p.Thr741Stop (T741X) (Chromosome 17:66902243).15 These 3 probands, who were heterozygous carriers of 3 different ABCA8 variants, formed the basis for further studies.
Figure 1. Mutations in adenosine triphosphate–binding cassette transporter A8 (ABCA8) result in low high-density lipoprotein cholesterol (HDLc), HDL particle size, and concentration in families. A, Predicted topographical model of ABCA8 with identified mutations. B, Plasma HDLc levels in heterozygous ABCA8 mutation carriers and first-degree relative controls. C, Mean HDL particle size, and (D) concentration of large HDL particles as assessed by nuclear magnetic resonance spectroscopy. Averages and standard errors are shown.
To investigate whether these 3 variants are deleterious, we first determined their frequencies in the dbSNP, 1000 genome, and exome variant server databases. The P609R variant is rare (minor allele frequency: 0.001 in the exome variant server population), while the c.IVS17-2 A>G and T741X variants were not found. Mutation functional prediction algorithms predicted the P609R variant to be “probably damaging,” while c.IVS17-2 A>G was predicted to abolish an essential splice site. T741X results in the truncation of more than half the protein, including adenosine triphosphate–binding cassette domain 2, which is likely to cause a large functional defect (Figure 1A). Across vertebrate genomes, both Pro609 and the nucleotide A in IVS17-2 A>G are conserved. Together, the in silico data suggest that all 3 variants are likely to be deleterious.

HDL Cholesterol Levels Are Decreased in ABCA8 Mutation Carriers

To investigate whether these mutations may underlie reduced HDLc levels, we first assessed their segregation with HDLc levels in 44 family members of the 3 probands (pedigrees in Figure I in the online-only Data Supplement). Heterozygous ABCA8 mutation carriers showed significantly reduced plasma HDLc levels compared with first-degree relative controls (0.86±0.34 mmol/L, n=15 versus 1.17±0.26, n=32; P=0.005; Figure 1B). Statistical significance remained when the original probands were excluded from the analyses (carriers: 0.95±0.28 mmol/L, n=12; P=0.018), indicating that plasma HDLc levels are significantly decreased in ABCA8 mutation carriers.
We next assessed plasma lipids and apolipoproteins. Plasma levels of apoA-I were, on average, 26.4% lower in mutation carriers compared with controls (carriers: 0.039±0.009 mmol/L, n=2; controls: 0.0523±0.008, n=9; Table 1), although few samples were measured because of limited availability of human plasma samples. No significant differences were observed in low-density lipoprotein cholesterol (LDLc), triglycerides, total cholesterol, and apolipoprotein B levels (Table 1).
Table 1. Basic Characteristics, and Plasma Lipid and Lipoprotein Levels in ABCA8 Mutation Carriers and First-Degree Relative Controls
 Heterozygous ABCA8 Mutation CarriersFirst-Degree Relative ControlsP Value
Age50.2±17.648.1±24.10.8
% male73.346.90.1
HDLc, mmol/L0.86±0.341.17±0.260.005
HDLc percentile15.5±18.134.8±21.40.001
TC, mmol/L4.49±1.194.77±0.930.5
LDLc, mmol/L2.94±0.853.12±0.700.6
TG, mmol/L1.65±1.601.24±0.600.08
ApoA-I, mmol/L0.039±0.0090.0523±0.008
ApoB, mmol/L0.0014±0.00020.002±0.0004
BMI, kg/m225.2±3.825.0±5.00.9
The P value for age was calculated using t test, and Fisher’s exact χ2 test was used to calculate the P value for % male. All other P values were generated using a mixed linear model to adjust for correlation between individuals in the same family. End point P values are controlled for age and sex. TG values were log transformed before statistical analyses. Data are presented as mean±SD and statistically significant values are in bold. ApoA-I indicates apolipoprotein AI; ApoB, apolipoprotein B; BMI, body mass index; HDLc, high-density lipoprotein cholesterol; LDLc, low-density lipoprotein cholesterol; TC, total cholesterol; and TG, triglycerides.

ABCA8 Mutations Associate With Reduced Large HDL Particle Concentration and HDL Particle Size

The association of ABCA8 mutations with HDL particle number, size, and composition was analyzed by means of nuclear magnetic resonance spectroscopy.17 HDL derived from heterozygous ABCA8 mutation carriers was significantly smaller than HDL from first-degree relative controls (carriers: 8.7±0.2 nm, n=9; controls: 9.2±0.4 nm, n=17; P=0.004; Figure 1C), which in turn was associated with lower large HDL particle concentration (carriers: 2.7±1.3, n=9; controls: 5.1±2.6 μmol/L, n=17; P=0.02; Figure 1D). No significant differences in total HDL particle concentration, LDL or very low-density lipoprotein particle size and concentration were observed.

Plasma HDLc levels Are Reduced in Abca8b Knockout Mice

To validate the direct relationship between ABCA8 and HDLc levels, we generated mice with a targeted deletion of Abca8b. Two tandem gene orthologs exist for ABCA8 in mice, Abca8a and Abca8b. Abca8b shows 75% identity with ABCA8, whereas Abca8a shows 68% identity. Thus, Abca8b was selected for initial knockout mouse generation. Absence of Abca8b expression in tissues including the liver was confirmed by reverse transcription polymerase chain reaction in Abca8b−/− mice (Figure II in the online-only Data Supplement). No changes in plasma HDLc levels were observed in Abca8b−/−mice compared with littermate controls on a chow diet (Abca8b+/+: 1.53±0.46; Abca8b-/-: 1.44±0.35 mmol/L; P=0.577). However, when placed on a high-cholesterol diet, Abca8b−/− mice showed a significant, 29% lower plasma HDLc level compared with wild-type controls (Abca8b+/+: 4.46±0.35; Abca8b−/−: 3.17±0.31 mmol/L; P=0.01; Figure 2A). In addition, total cholesterol, LDLc, and triglyceride levels were also reduced in Abca8b−/− mice (Table 2). No significant changes in the expression of hepatic Abca8a and Abca1 were observed (Figure II in the online-only Data Supplement).
Table 2. Plasma Lipid Levels in Abca8b−/− Mice on High-Cholesterol Diet
 Abca8b+/+Abca8b−/−P Value
TC4.74±0.373.39±0.340.02
HDLc4.46±0.353.17±0.310.01
LDLc0.88±0.090.58±0.080.02
TG0.80±0.040.69±0.020.03
Data are presented as mean±SD in mmol/L. HDLc indicates high-density lipoprotein cholesterol; TC, total cholesterol; LDLc, low-density lipoprotein cholesterol; and TG, triglycerides.
Figure 2. Adenosine triphosphate–binding cassette transporter A8 (ABCA8) expression modulates plasma high-density lipoprotein cholesterol (HDLc) levels. A, Plasma HDLc levels in Abca8b−/− and wild-type mice fed a high-cholesterol diet. Data are presented as mean±SEM. BE, Adenoviral human ABCA8 was delivered by tail vein to wild-type mice, and liver-specific expression was observed by (B) reverse transcription polymerase chain reaction (n=4–14), and (C) western immunoblotting 72 h after injection. HDLc (D) and total cholesterol (E) levels in control and ABCA8 overexpressing mice 24 hours after injection.

Hepatic ABCA8 Overexpression in Mice Significantly Increases Plasma HDLc Levels

We next determined the tissue distribution of human ABCA8 and the mouse orthologs Abca8a and Abca8b. We found high human ABCA8 mRNA levels in the heart, as well as in the liver and skeletal muscle (Figure IIIA in the online-only Data Supplement), in line with previous observations.18 Mouse Abca8a and Abca8b expression was highest in the liver, and was also abundant in heart and skeletal muscle (Figure IIIB, C in the online-only Data Supplement), in agreement with the human tissue distribution profile and with previous observations.19 Since this is the first report studying Abca8b−/− mice and the expression of Abca8b is high in the heart and skeletal muscle, we assessed the organ/body mass ratio and performed gross pathology of these 2 tissues. No macroscopic differences were observed in heart or skeletal muscle from Abca8b−/− compared with wild-type mice (data not shown). Because mutations in ABCA8 are associated with lower plasma HDLc levels, and both human and mouse ABCA8 genes are highly expressed in the liver, we hypothesized that hepatic ABCA8 overexpression would significantly increase HDLc levels. Hepatic overexpression of human ABCA8 in wild-type mice via adenoviral (Ad) injection resulted in the expression of human ABCA8 predominantly in the liver (Figure 2B, 2C). Both plasma HDLc (Figure 2D) and total cholesterol (Figure 2E) were significantly increased 24 hours after Ad-ABCA8 infection compared with baseline (23.1%, P=0.007, and 13.8%, P=0.02, respectively). Forty hours postinfection, HDLc levels normalized. No significant changes in non-HDLc levels were observed.

Early Steps of Macrophage-to-Feces RCT Are Significantly Increased in Mice With Hepatic ABCA8 Overexpression

As liver-specific overexpression of ABCA8 resulted in significantly increased plasma HDLc levels in mice, we investigated whether an increase in macrophage-to-feces RCT occurred when human ABCA8 was overexpressed in the liver of wild-type mice. After injection of [3H]-cholesterol-loaded macrophages, a significant 50% increase in plasma [3H] counts was observed in mice with hepatic ABCA8 overexpression (ABCA8: 3.9±0.2, controls: 2.6±0.2, % of injected dose, P<0.01 at 48 hours, Figure 3A). To compare the ability of ABCA1 to facilitate RCT in the same model, we also determined if increased macrophage-to-feces RCT occurred when ABCA1 was adenovirally overexpressed in the liver of wild-type mice. As with ABCA8, increased plasma [3H] counts were also observed in mice overexpressing hepatic ABCA1 (ABCA1: 4.2±0.2, controls: 2.6±0.2, % of injected dose, P<0.001 at 48 hours, Figure 3A). Liver [3H] counts were also significantly increased in the mice overexpressing either hepatic ABCA8 (ABCA8: 2.4±0.1, controls: 1.7±0.2, % of injected dose, P<0.01 at 48 hours, Figure 3B) or ABCA1 (ABCA1: 2.1±0.1, controls: 1.7±0.2, % of injected dose, P<0.05 at 48 hours, Figure 3B). However, despite the increased plasma and liver counts, no significant changes in fecal bile acid or neutral sterol counts were observed in either model (Figure 3C), indicating that in our model, hepatic overexpression of either ABCA8 or ABCA1 affects mainly the early steps of the RCT pathway.
Figure 3. Hepatic Adenosine triphosphate–binding cassette transporter A8 (ABCA8) and Adenosine triphosphate–binding cassette transporter A1 (ABCA1) increase the early steps of in vivo reverse cholesterol transport. A, Significantly increased plasma [3H] counts at 48 h in mice with hepatic overexpression of human ABCA8 or human ABCA1. B, Significantly increased liver [3H] counts in the liver-specific ABCA8 or ABCA1 overexpressing mice. C, Unchanged fecal [3H] counts in mice with ABCA8 or ABCA1 liver-specific overexpression. n=7 each. Mean and standard errors are shown.

ABCA8 Localizes to the Plasma Membrane and Endoplasmic Reticulum and Facilitates Cholesterol Efflux to Lipid-Free ApoA-I

Since mutations in ABCA8, like ABCA1, are associated with low plasma HDLc levels, and ABCA1 is a well-established plasma membrane (PM) localized lipid efflux protein, we hypothesized that ABCA8 might also localize at the PM and regulate cellular cholesterol transport. When expressed in COS-7 cells, ABCA8 was indeed localized at the PM and also colocalized with calnexin,20 indicating endoplasmic reticulum localization (Figure IV in the online-only Data Supplement). In contrast, ABCA8 harboring the P609R mutation was almost exclusively identified intracellularly, and colocalized with calnexin, indicating defective cell surface expression (Figure IV in the online-only Data Supplement). We failed to detect T741X (Figure IV in the online-only Data Supplement), suggesting that the full-length T741X protein is not expressed. To determine if the first 741 amino acids in T741X are expressed, we generated T741-V5-X, with the V5 tag replacing the mutant stop codon. Like P609R, T741-V5-X colocalized almost exclusively with calnexin in the endoplasmic reticulum, and was not detected at the PM (Figure IV in the online-only Data Supplement). Thus, ABCA8 encoding P609R or T741X fails to translocate to the cell surface. IVS17-2 A>G was not generated because we utilized a cDNA construct.
The ability of ABCA8 to localize at the PM suggests it could play a role in cholesterol efflux. Indeed, wild-type ABCA8 increased cholesterol efflux to ApoA-I by 181% when transfected into COS-7 cells (Figure 4A). In contrast, transfection of P609R or T741X resulted in efflux comparable to empty vector controls (Figure 4A). Thus, ABCA8 facilitates cholesterol efflux to ApoA-I, which is abolished by both P609R and T741X. To further confirm the role of ABCA8 in efflux, and to compare its efflux capacity to ABCA1, we assessed ApoA-I–mediated cholesterol efflux in fibroblasts isolated from ABCA8 and ABCA1 mutation carriers. Indeed, fibroblasts from heterozygous ABCA8 mutation carriers showed a 20% to 43% reduction in cholesterol efflux (Figure 4B). In comparison, cholesterol efflux from heterozygous ABCA1 mutation carrier fibroblasts was reduced by 53% on average (Figure 4B). The mutations in the ABCA1 carriers are IVS24+1 G>C, p.Asp575Gly, and IVS48+2 T>C, and are loss of function mutations identified in patients with Tangier disease or Familial Hypoalphalipoproteinemia.21,22 Our data suggest that ABCA1 is a more potent facilitator of cholesterol efflux compared with ABCA8, at least in fibroblasts. To confirm this difference in efflux capacity between ABCA1 and ABCA8, we overexpressed similar amounts of V5-ABCA8 and V5-ABCA1 as assessed by anti-V5 immunoblots. ABCA1 showed a 1.8-fold increase in efflux capacity compared with ABCA8 (Figure 4C), confirming that ABCA1 is a more potent cholesterol efflux protein. Moreover, cotransfection of the 2 proteins resulted in further enhanced cholesterol efflux (Figure 4C), suggesting that ABCA8 and ABCA1 together further augment cholesterol efflux to ApoA-I. To further determine the influence of ABCA8 on ABCA1 activity, we assessed cholesterol efflux to ApoA-I in fibroblast cultures established from control, ABCA8 heterozygote, ABCA1 heterozygote, and ABCA1 homozygote individuals in the presence/absence of the liver X receptor agonist TO-901317, which induces the expression of ABCA1 but not ABCA8. We observed that the ABCA1-specific cholesterol efflux decreased by 49% in fibroblasts from ABCA8 heterozygotes, and a similar 52% decrease was observed in fibroblasts from ABCA1 heterozygotes (Figure 4D). These findings indicate that the loss of a single ABCA8 allele has the same impact on ABCA1-specific efflux as the loss of a single ABCA1 allele, and suggest that ABCA1 and ABCA8 work together to regulate cholesterol efflux to ApoA-I.
Figure 4. Adenosine triphosphate–binding cassette transporter A8 (ABCA8) facilitates cholesterol efflux to lipid-free apolipoprotein AI (ApoA-I). A, Efflux of cholesterol to lipid-free ApoA-I in COS-7 cells transfected with wild-type and mutant human ABCA8. B, Efflux of cholesterol to lipid-free ApoA-I in fibroblasts isolated from heterozygous carriers of mutations in ABCA8 and ABCA1 and from control individuals. C, Efflux of cholesterol to lipid-free ApoA-I in COS-7 cells transfected with wild-type human ABCA8, ABCA1, or ABCA8+ABCA1 together. D, Adenosine triphosphate–binding cassette transporter A1–specific efflux of cholesterol to lipid-free ApoA-I in fibroblasts isolated from controls, ABCA8+/−, ABCA1+/−, and ABCA1−/− mutation carriers. ABCA1-specific efflux is calculated as the difference between efflux in the presence and the absence of the liver X receptor agonist TO-901317. Data in A to D shown as mean±SEM. E, Colocalization of overexpressed human ABCA8-V5 and ABCA1-GFP (green fluorescent protein) in HEK293T cells, visualized with anti-V5 and anti-GFP antibodies. F, Coimmunoprecipitation of human ABCA1 and ABCA8-V5 in HEK293T cells.

ABCA8 Colocalizes With and Interacts With ABCA1

Because ABCA8 and ABCA123 both localize at the PM and endoplasmic reticulum, facilitate cholesterol efflux to ApoA-I, and when expressed together, further enhance cholesterol efflux compared with each alone, and because a reduction in ABCA8 affects ABCA1-specific efflux, we hypothesized that they might interact. We first determined the subcellular colocalization of ABCA8 and ABCA1 by coexpressing both proteins with different tags (ABCA8-V5 and ABCA1-GFP [green fluorescent protein]) in HEK293T cells. Indeed, ABCA8 colocalizes completely with ABCA1 at the PM and intracellularly (Figure 4E). In addition, ABCA8 and ABCA1 coimmunoprecipitate when both proteins are coexpressed (Figure 4F). Thus, ABCA8 and ABCA1 act together in regulating cholesterol efflux.

Discussion

We describe here the identification and validation of ABCA8 as a cholesterol efflux protein that influences HDL metabolism in humans. Loss of function mutations in ABCA8 result in significantly lower plasma HDLc levels compared with noncarrier relative controls. In mice, hepatic overexpression of human ABCA8 resulted in a significant selective increase in plasma HDLc levels, whereas targeted deletion of the mouse ortholog Abca8b resulted in significantly reduced plasma HDLc levels.
ABCA8 shows several similarities with ABCA1, a protein with a well-established role in lipid efflux and HDL metabolism. Both proteins are found in the liver.24 Subcellularly, ABCA1 is localized to the PM, endoplasmic reticulum, and endocytic vesicles.23 Its localization at the PM is essential for its role in cholesterol efflux, and mutations disrupting this PM localization result in significantly reduced cholesterol efflux.25 A similar subcellular distribution pattern and impact on cholesterol efflux is observed for ABCA8. Both ABCA8 and ABCA1 facilitate the efflux of cholesterol to lipid-free ApoA-I, and our data suggest that ABCA1 is the more efficient cholesterol efflux protein. A previous study found that ABCA8 was also capable of significantly increasing cholesterol efflux, albeit not specifically to either ApoA-I or apolipoprotein E.26
In humans, mutations in either ABCA1 or ABCA8 result in significantly lower plasma HDLc. While some pedigrees lacked statistical power to assess Mendelian segregation of mutations with HDLc levels, across all pedigrees, we observed a significant 27% lower plasma HDLc levels in heterozygous ABCA8 mutation carriers, which is comparable to our previous observations of ≈40% lower HDLc in heterozygous ABCA1 mutation carriers.27 Mutations in ABCA8, similar to ABCA1,28 result in decreased large HDL particle concentration and reduced HDL particle size. Complete deletion of mouse Abca1 results in a 99.5% reduction in HDLc levels on a western-type diet,29 while a 29% decrease in HDLc was observed in Abca8b−/− mice on a high-cholesterol diet. The difference in the HDLc level between Abca8b−/− and Abca1−/− mice might be explained by ABCA8’s lower relative efflux capacity. In addition, in mice, 2 orthologous genes exist for human ABCA8, Abca8a, and Abca8b, and it is possible that in the Abca8b−/− mice, Abca8a might contribute to plasma HDLc levels. Abca8b−/− mice on a high-cholesterol diet also show lower LDLc levels compared with wild-type mice, whereas ABCA8 mutation carriers present a very specific decrease only in HDLc, but not in LDLc. The lower LDLc levels in the Abca8b−/− mice might be because of an accelerated LDL catabolism, similar to previous observations in hepatic Abca1−/− mice.30
When either ABCA8 or ABCA1 are overexpressed in the liver of mice, the movement of labeled cholesterol from macrophages to the plasma and liver, the early steps in RCT, is significantly elevated. Similarly, systemic increases in Abca1 expression stimulate macrophage-to-feces RCT in mice,31 while the absence of Abca1 in mice leads to decreased RCT.32,33 Because ABCA8 and ABCA1 were overexpressed exclusively in liver and not in macrophages, our data suggest that liver ABCA8, like liver ABCA1, facilitates the generation of a particle with the ability to take up lipids from macrophages. However, this increase in the initial steps of RCT did not result in changes in fecal counts. While the reasons for this observation warrant further study, liver-specific Abca1 deletion also did not decrease macrophage-to-feces RCT.34
Based on the similarities between ABCA1 and ABCA8, the specific functions of each protein remain a key question. HDLc levels are extremely low in the absence of ABCA1, both in Tangier disease patients and Abca1−/− mice,35 suggesting that ABCA8 does not compensate for the absence of ABCA1. This, together with our finding that ABCA8 and ABCA1 interact, suggest that these 2 proteins are unlikely to be operating in completely independent pathways to modulate HDLc levels, but rather, may act via overlapping pathways.
One possibility for the overlapping pathway hypothesis is that ABCA1 and ABCA8 act together as a complex or regulate each other’s function. This hypothesis is not without precedent. ABCA12, a transporter of glucosylceramide, interacts with, and regulates ABCA1’s cholesterol transporter function in macrophages, and ABCA12 deficiency results in impaired RCT and macrophage foam cell formation.36,37 It is thought that ABCA12 modulates ABCA1 function via its binding to ABCA1 and increasing the protein levels and stability of ABCA1. If ABCA8 plays a similar role, then a similar phenotype would be expected in either the absence of ABCA1 or ABCA8. However, reduced ABCA8 has a milder impact on plasma HLDc levels and cholesterol efflux when compared with reduced ABCA1 levels. Thus, another possibility for the regulation of ABCA1 function by ABCA8 could be that ABCA8 transports lipids, perhaps sphingomyelin,26 to or in the PM, to form specific membrane domains, thus contributing to the lipid composition of these membrane domains and creating regions from which ABCA1 can then transport lipids to ApoA-I.
This model also may explain the increased cholesterol efflux capacity of ABCA1 compared with ABCA8. Of the 2 proteins, ABCA1 may be the primary cholesterol transporter, and the absence of ABCA1 results in a large reduction in cholesterol efflux. ABCA8 may affect the cholesterol pool size available for ABCA1-mediated efflux via the transport of another lipid species. Thus, in the absence of ABCA8, a smaller impact on cholesterol efflux is observed. This model also fits with the observation of additional enhancement in cholesterol efflux when both ABCA8 and ABCA1 are overexpressed.
There are some differences between mouse and human lipoprotein metabolism. For example, mice carry most of their plasma cholesterol in HDL particles, whereas humans carry most of their plasma cholesterol in LDL particles, because of a lack of cholesteryl ester transfer protein in mice.38 Cholesteryl ester transfer protein transfers cholesterol esters from HDL to LDL or very low-density lipoprotein particles. This and other differences are limitations to translating our observations directly from mice to humans and vice versa. Indeed, we do observe some differences between the results in our human or mouse models. A humanized mouse such as CETP transgenic mice crossed to our Abca8b−/− mice would further facilitate the translation of our findings.
The identification of deleterious mutations in ABCA8 as a novel cause of reduced plasma HDLc in humans adds a piece to the intriguing puzzle of HDL metabolism. Our data indicate that ABCA8 interacts with ABCA1 and regulates its efflux capacity. Whether this has an impact on atherosclerosis progression remains to be seen.

Highlights

Adenosine triphosphate–binding cassette transporter A8 regulates high-density lipoprotein cholesterol levels in humans and mice.
Adenosine triphosphate–binding cassette transporter A8 facilitates cholesterol efflux to lipid-free apolipoprotein AI.
Adenosine triphosphate–binding cassette transporter A8 interacts with adenosine triphosphate–binding cassette transporter A1, and further potentiates cholesterol efflux.

Acknowledgments

We thank all study participants. We also thank K. Los for the genetic fieldwork, and J. Peter, Amber Anushree Eliathamby, and Tricia Chua for technical assistance. Microscopy images were acquired at the SBIC-Nikon Imaging Centre at A*STAR.

Supplemental Material

File (atvb_atvb-2017-309574_supp1.pdf)
File (atvb_atvb-2017-309574_supp2.pdf)

References

1.
Rosamond W, Flegal K, Friday G, et al.; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics–2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2007;115:e69–e171. doi: 10.1161/CIRCULATIONAHA.106.179918.
2.
Lewington S, Whitlock G, Clarke R, Sherliker P, Emberson J, Halsey J, Qizilbash N, Peto R, Collins R. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet. 2007:370:1829–1839.
3.
Hovingh GK, Ray KK, Boekholdt SM. Is cholesteryl ester transfer protein inhibition an effective strategy to reduce cardiovascular risk? CETP as a target to lower CVD risk: suspension of disbelief? Circulation. 2015;132:433–440. doi: 10.1161/CIRCULATIONAHA.115.014026.
4.
Vergeer M, Holleboom AG, Kastelein JJ, Kuivenhoven JA. The HDL hypothesis: does high-density lipoprotein protect from atherosclerosis? J Lipid Res. 2010;51:2058–2073. doi: 10.1194/jlr.R001610.
5.
Gui T, Shimokado A, Sun Y, Akasaka T, Muragaki Y. Diverse roles of macrophages in atherosclerosis: from inflammatory biology to biomarker discovery. Mediators Inflamm. 2012;2012:693083. doi: 10.1155/2012/693083.
6.
Schmitz G, Grandl M. Lipid homeostasis in macrophages - implications for atherosclerosis. Rev Physiol Biochem Pharmacol. 2008;160:93–125. doi: 10.1007/112_2008_802.
7.
von Eckardstein A, Nofer JR, Assmann G. High density lipoproteins and arteriosclerosis. Role of cholesterol efflux and reverse cholesterol transport. Arterioscler Thromb Vasc Biol. 2001;21:13–27.
8.
Khera AV, Cuchel M, de la Llera-Moya M, Rodrigues A, Burke MF, Jafri K, French BC, Phillips JA, Mucksavage ML, Wilensky RL, Mohler ER, Rothblat GH, Rader DJ. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N Engl J Med. 2011;364:127–135. doi: 10.1056/NEJMoa1001689.
9.
Rohatgi A, Khera A, Berry JD, Givens EG, Ayers CR, Wedin KE, Neeland IJ, Yuhanna IS, Rader DR, de Lemos JA, Shaul PW. HDL cholesterol efflux capacity and incident cardiovascular events. N Engl J Med. 2014;371:2383–2393. doi: 10.1056/NEJMoa1409065.
10.
Li XM, Tang WH, Mosior MK, Huang Y, Wu Y, Matter W, Gao V, Schmitt D, Didonato JA, Fisher EA, Smith JD, Hazen SL. Paradoxical association of enhanced cholesterol efflux with increased incident cardiovascular risks. Arterioscler Thromb Vasc Biol. 2013;33:1696–1705. doi: 10.1161/ATVBAHA.113.301373.
11.
Tall AR, Yvan-Charvet L, Terasaka N, Pagler T, Wang N. HDL, ABC transporters, and cholesterol efflux: implications for the treatment of atherosclerosis. Cell Metab. 2008;7:365–375. doi: 10.1016/j.cmet.2008.03.001.
12.
Wang S, Smith JD. ABCA1 and nascent HDL biogenesis. Biofactors. 2014;40:547–554. doi: 10.1002/biof.1187.
13.
Weissglas-Volkov D, Pajukanta P. Genetic causes of high and low serum HDL-cholesterol. J Lipid Res. 2010;51:2032–2057. doi: 10.1194/jlr.R004739.
14.
Teslovich TM, Musunuru K, Smith AV, et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature. 2010;466:707–713. doi: 10.1038/nature09270.
15.
Motazacker MM, Peter J, Treskes M, Shoulders CC, Kuivenhoven JA, Hovingh GK. Evidence of a polygenic origin of extreme high-density lipoprotein cholesterol levels. Arterioscler Thromb Vasc Biol. 2013;33:1521–1528. doi: 10.1161/ATVBAHA.113.301505.
16.
Singaraja RR, Tietjen I, Hovingh GK, et al. Identification of four novel genes contributing to familial elevated plasma HDL cholesterol in humans. J Lipid Res. 2014;55:1693–1701. doi: 10.1194/jlr.M048710.
17.
Otvos JD. Measurement of lipoprotein subclass profiles by nuclear magnetic resonance spectroscopy. Clin Lab. 2002;48:171–180.
18.
Tsuruoka S, Ishibashi K, Yamamoto H, Wakaumi M, Suzuki M, Schwartz GJ, Imai M, Fujimura A. Functional analysis of ABCA8, a new drug transporter. Biochem Biophys Res Commun. 2002;298:41–45.
19.
Annilo T, Chen ZQ, Shulenin S, Dean M. Evolutionary analysis of a cluster of ATP-binding cassette (ABC) genes. Mamm Genome. 2003;14:7–20. doi: 10.1007/s00335-002-2229-9.
20.
David V, Hochstenbach F, Rajagopalan S, Brenner MB. Interaction with newly synthesized and retained proteins in the endoplasmic reticulum suggests a chaperone function for human integral membrane protein IP90 (calnexin). J Biol Chem. 1993;268:9585–9592.
21.
Marcil M, Brooks-Wilson A, Clee SM, et al. Mutations in the ABC1 gene in familial HDL deficiency with defective cholesterol efflux. Lancet. 1999;354:1341–1346.
22.
Candini C, Schimmel AW, Peter J, Bochem AE, Holleboom AG, Vergeer M, Dullaart RP, Dallinga-Thie GM, Hovingh GK, Khoo KL, Fasano T, Bocchi L, Calandra S, Kuivenhoven JA, Motazacker MM. Identification and characterization of novel loss of function mutations in ATP-binding cassette transporter A1 in patients with low plasma high-density lipoprotein cholesterol. Atherosclerosis. 2010;213:492–498. doi: 10.1016/j.atherosclerosis.2010.08.062.
23.
Neufeld EB, Remaley AT, Demosky SJ, Stonik JA, Cooney AM, Comly M, Dwyer NK, Zhang M, Blanchette-Mackie J, Santamarina-Fojo S, Brewer HB Cellular localization and trafficking of the human ABCA1 transporter. J Biol Chem. 2001;276:27584–27590. doi: 10.1074/jbc.M103264200.
24.
Wellington CL, Walker EK, Suarez A, Kwok A, Bissada N, Singaraja R, Yang YZ, Zhang LH, James E, Wilson JE, Francone O, McManus BM, Hayden MR. ABCA1 mRNA and protein distribution patterns predict multiple different roles and levels of regulation. Lab Invest. 2002;82:273–283.
25.
Singaraja RR, Visscher H, James ER, Chroni A, Coutinho JM, Brunham LR, Kang MH, Zannis VI, Chimini G, Hayden MR. Specific mutations in ABCA1 have discrete effects on ABCA1 function and lipid phenotypes both in vivo and in vitro. Circ Res. 2006;99:389–397. doi: 10.1161/01.RES.0000237920.70451.ad.
26.
Kim WS, Hsiao JH, Bhatia S, Glaros EN, Don AS, Tsuruoka S, Shannon Weickert C, Halliday GM. ABCA8 stimulates sphingomyelin production in oligodendrocytes. Biochem J. 2013;452:401–410. doi: 10.1042/BJ20121764.
27.
Tietjen I, Hovingh GK, Singaraja R, Radomski C, McEwen J, Chan E, Mattice M, Legendre A, Kastelein JJ, Hayden MR. Increased risk of coronary artery disease in Caucasians with extremely low HDL cholesterol due to mutations in ABCA1, APOA1, and LCAT. Biochim Biophys Acta. 2012;1821:416–424. doi: 10.1016/j.bbalip.2011.08.006.
28.
Kuivenhoven JA, Hovingh GK, van Tol A, Jauhiainen M, Ehnholm C, Fruchart JC, Brinton EA, Otvos JD, Smelt AH, Brownlee A, Zwinderman AH, Hayden MR, Kastelein JJ. Heterozygosity for ABCA1 gene mutations: effects on enzymes, apolipoproteins and lipoprotein particle size. Atherosclerosis. 2003;171:311–319.
29.
McNeish J, Aiello RJ, Guyot D, Turi T, Gabel C, Aldinger C, Hoppe KL, Roach ML, Royer LJ, de Wet J, Broccardo C, Chimini G, Francone OL. High density lipoprotein deficiency and foam cell accumulation in mice with targeted disruption of ATP-binding cassette transporter-1. Proc Natl Acad Sci USA. 2000;97:4245–4250.
30.
Chung S, Timmins JM, Duong M, Degirolamo C, Rong S, Sawyer JK, Singaraja RR, Hayden MR, Maeda N, Rudel LL, Shelness GS, Parks JS. Targeted deletion of hepatocyte ABCA1 leads to very low density lipoprotein triglyceride overproduction and low density lipoprotein hypercatabolism. J Biol Chem. 2010;285:12197–12209. doi: 10.1074/jbc.M109.096933.
31.
Naik SU, Wang X, Da Silva JS, Jaye M, Macphee CH, Reilly MP, Billheimer JT, Rothblat GH, Rader DJ. Pharmacological activation of liver X receptors promotes reverse cholesterol transport in vivo. Circulation. 2006;113:90–97. doi: 10.1161/CIRCULATIONAHA.105.560177.
32.
Wang MD, Franklin V, Marcel YL. In vivo reverse cholesterol transport from macrophages lacking ABCA1 expression is impaired. Arterioscler Thromb Vasc Biol. 2007;27:1837–1842. doi: 10.1161/ATVBAHA.107.146068.
33.
Wang X, Collins HL, Ranalletta M, Fuki IV, Billheimer JT, Rothblat GH, Tall AR, Rader DJ. Macrophage ABCA1 and ABCG1, but not SR-BI, promote macrophage reverse cholesterol transport in vivo. J Clin Invest. 2007;117:2216–2224. doi: 10.1172/JCI32057.
34.
Bi X, Zhu X, Duong M, Boudyguina EY, Wilson MD, Gebre AK, Parks JS. Liver ABCA1 deletion in LDLrKO mice does not impair macrophage reverse cholesterol transport or exacerbate atherogenesis. Arterioscler Thromb Vasc Biol. 2013;33:2288–2296. doi: 10.1161/ATVBAHA.112.301110.
35.
Alan D. Attie. ABCA1: at the nexus of cholesterol, HDL and atherosclerosis. Trends Biochem Sci. 2007:32:172–179.
36.
Fu Y, Mukhamedova N, Ip S, D’Souza W, Henley KJ, DiTommaso T, Kesani R, Ditiatkovski M, Jones L, Lane RM, Jennings G, Smyth IM, Kile BT, Sviridov D. ABCA12 regulates ABCA1-dependent cholesterol efflux from macrophages and the development of atherosclerosis. Cell Metab. 2013;18:225–238. doi: 10.1016/j.cmet.2013.07.003.
37.
Smyth I, Hacking DF, Hilton AA, Mukhamedova N, Meikle PJ, Ellis S, Satterley K, Slattery K, Collinge JE, de Graaf CA, Bahlo M, Sviridov D, Kile BT, Hilton DJ. A mouse model of harlequin ichthyosis delineates a key role for Abca12 in lipid homeostasis. PLoS Genet. 2008;4:e1000192. doi: 10.1371/journal.pgen.1000192.
38.
Guyard-Dangremont V, Desrumaux C, Gambert P, Lallemant C, Lagrost L. Phospholipid and cholesteryl ester transfer activities in plasma from 14 vertebrate species. Relation to atherogenesis susceptibility. Comp Biochem Physiol B Biochem Mol Biol. 1998;120:517–525.

eLetters(0)

eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.

Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.

Information & Authors

Information

Published In

Go to Arteriosclerosis, Thrombosis, and Vascular Biology
Go to Arteriosclerosis, Thrombosis, and Vascular Biology

Immunostaining of a whole-mounted retina from a Cx40-deficient mouse at postnatal day 6, showing the labeling of newly formed vessels for isolectin-B4 (cyan), CD31 (magenta), and PDGFR-β (green). Nuclei are visualized with Hoechst (blue). (See pages 2136–2146.)

Arteriosclerosis, Thrombosis, and Vascular Biology
Pages: 2147 - 2155
PubMed: 28882873

Versions

You are viewing the most recent version of this article.

History

Received: 25 April 2017
Accepted: 29 August 2017
Published online: 7 September 2017
Published in print: November 2017

Permissions

Request permissions for this article.

Keywords

  1. atherosclerosis
  2. ATP-binding cassette transporters
  3. cholesterol, HDL
  4. reverse cholesterol transport

Subjects

Authors

Affiliations

Laia Trigueros-Motos
From the Translational Laboratory in Genetic Medicine, A*STAR Institute, and Yong Loo Lin School of Medicine, National University of Singapore (L.T.-M., D.C., E.C.C., L.J.T., D.H.W., G.K.Y., M.R.H., R.R.S.); Departments of Vascular Medicine and Experimental Vascular Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands (J.C.v.C., A.W.M.S., G.M.D.-T., G.K.H.); Faculty of Health Sciences, Simon Fraser University, Canada (I.T.); Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (F.T., P.N., M.R.W.); Centre for Molecular Medicine and Therapeutics and Child and Family Research Institute, University of British Columbia, Canada (L.-H.Z., M.K., M.R.H.); Department of Pediatrics, University Medical Center Groningen, University of Groningen, The Netherlands (L.G.D., U.J.F.T.); Xenon Pharmaceuticals, Burnaby, Canada (I.T., C.R.); Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore (C.H.T., V.A.); Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Austria (F.D., J.B.); Beaulieu-Saucier Université de Montréal Pharmacogenomics Centre, Canada (A.B., M.-P.D.); Montréal Heart Institute Research Centre, Canada (A.B., M.-P.D.); and Université de Montréal, Canada (A.B., M.-P.D.).
Julian C. van Capelleveen
From the Translational Laboratory in Genetic Medicine, A*STAR Institute, and Yong Loo Lin School of Medicine, National University of Singapore (L.T.-M., D.C., E.C.C., L.J.T., D.H.W., G.K.Y., M.R.H., R.R.S.); Departments of Vascular Medicine and Experimental Vascular Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands (J.C.v.C., A.W.M.S., G.M.D.-T., G.K.H.); Faculty of Health Sciences, Simon Fraser University, Canada (I.T.); Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (F.T., P.N., M.R.W.); Centre for Molecular Medicine and Therapeutics and Child and Family Research Institute, University of British Columbia, Canada (L.-H.Z., M.K., M.R.H.); Department of Pediatrics, University Medical Center Groningen, University of Groningen, The Netherlands (L.G.D., U.J.F.T.); Xenon Pharmaceuticals, Burnaby, Canada (I.T., C.R.); Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore (C.H.T., V.A.); Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Austria (F.D., J.B.); Beaulieu-Saucier Université de Montréal Pharmacogenomics Centre, Canada (A.B., M.-P.D.); Montréal Heart Institute Research Centre, Canada (A.B., M.-P.D.); and Université de Montréal, Canada (A.B., M.-P.D.).
Federico Torta
From the Translational Laboratory in Genetic Medicine, A*STAR Institute, and Yong Loo Lin School of Medicine, National University of Singapore (L.T.-M., D.C., E.C.C., L.J.T., D.H.W., G.K.Y., M.R.H., R.R.S.); Departments of Vascular Medicine and Experimental Vascular Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands (J.C.v.C., A.W.M.S., G.M.D.-T., G.K.H.); Faculty of Health Sciences, Simon Fraser University, Canada (I.T.); Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (F.T., P.N., M.R.W.); Centre for Molecular Medicine and Therapeutics and Child and Family Research Institute, University of British Columbia, Canada (L.-H.Z., M.K., M.R.H.); Department of Pediatrics, University Medical Center Groningen, University of Groningen, The Netherlands (L.G.D., U.J.F.T.); Xenon Pharmaceuticals, Burnaby, Canada (I.T., C.R.); Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore (C.H.T., V.A.); Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Austria (F.D., J.B.); Beaulieu-Saucier Université de Montréal Pharmacogenomics Centre, Canada (A.B., M.-P.D.); Montréal Heart Institute Research Centre, Canada (A.B., M.-P.D.); and Université de Montréal, Canada (A.B., M.-P.D.).
David Castaño
From the Translational Laboratory in Genetic Medicine, A*STAR Institute, and Yong Loo Lin School of Medicine, National University of Singapore (L.T.-M., D.C., E.C.C., L.J.T., D.H.W., G.K.Y., M.R.H., R.R.S.); Departments of Vascular Medicine and Experimental Vascular Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands (J.C.v.C., A.W.M.S., G.M.D.-T., G.K.H.); Faculty of Health Sciences, Simon Fraser University, Canada (I.T.); Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (F.T., P.N., M.R.W.); Centre for Molecular Medicine and Therapeutics and Child and Family Research Institute, University of British Columbia, Canada (L.-H.Z., M.K., M.R.H.); Department of Pediatrics, University Medical Center Groningen, University of Groningen, The Netherlands (L.G.D., U.J.F.T.); Xenon Pharmaceuticals, Burnaby, Canada (I.T., C.R.); Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore (C.H.T., V.A.); Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Austria (F.D., J.B.); Beaulieu-Saucier Université de Montréal Pharmacogenomics Centre, Canada (A.B., M.-P.D.); Montréal Heart Institute Research Centre, Canada (A.B., M.-P.D.); and Université de Montréal, Canada (A.B., M.-P.D.).
Lin-Hua Zhang
From the Translational Laboratory in Genetic Medicine, A*STAR Institute, and Yong Loo Lin School of Medicine, National University of Singapore (L.T.-M., D.C., E.C.C., L.J.T., D.H.W., G.K.Y., M.R.H., R.R.S.); Departments of Vascular Medicine and Experimental Vascular Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands (J.C.v.C., A.W.M.S., G.M.D.-T., G.K.H.); Faculty of Health Sciences, Simon Fraser University, Canada (I.T.); Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (F.T., P.N., M.R.W.); Centre for Molecular Medicine and Therapeutics and Child and Family Research Institute, University of British Columbia, Canada (L.-H.Z., M.K., M.R.H.); Department of Pediatrics, University Medical Center Groningen, University of Groningen, The Netherlands (L.G.D., U.J.F.T.); Xenon Pharmaceuticals, Burnaby, Canada (I.T., C.R.); Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore (C.H.T., V.A.); Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Austria (F.D., J.B.); Beaulieu-Saucier Université de Montréal Pharmacogenomics Centre, Canada (A.B., M.-P.D.); Montréal Heart Institute Research Centre, Canada (A.B., M.-P.D.); and Université de Montréal, Canada (A.B., M.-P.D.).
Ee Chu Chai
From the Translational Laboratory in Genetic Medicine, A*STAR Institute, and Yong Loo Lin School of Medicine, National University of Singapore (L.T.-M., D.C., E.C.C., L.J.T., D.H.W., G.K.Y., M.R.H., R.R.S.); Departments of Vascular Medicine and Experimental Vascular Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands (J.C.v.C., A.W.M.S., G.M.D.-T., G.K.H.); Faculty of Health Sciences, Simon Fraser University, Canada (I.T.); Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (F.T., P.N., M.R.W.); Centre for Molecular Medicine and Therapeutics and Child and Family Research Institute, University of British Columbia, Canada (L.-H.Z., M.K., M.R.H.); Department of Pediatrics, University Medical Center Groningen, University of Groningen, The Netherlands (L.G.D., U.J.F.T.); Xenon Pharmaceuticals, Burnaby, Canada (I.T., C.R.); Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore (C.H.T., V.A.); Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Austria (F.D., J.B.); Beaulieu-Saucier Université de Montréal Pharmacogenomics Centre, Canada (A.B., M.-P.D.); Montréal Heart Institute Research Centre, Canada (A.B., M.-P.D.); and Université de Montréal, Canada (A.B., M.-P.D.).
Martin Kang
From the Translational Laboratory in Genetic Medicine, A*STAR Institute, and Yong Loo Lin School of Medicine, National University of Singapore (L.T.-M., D.C., E.C.C., L.J.T., D.H.W., G.K.Y., M.R.H., R.R.S.); Departments of Vascular Medicine and Experimental Vascular Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands (J.C.v.C., A.W.M.S., G.M.D.-T., G.K.H.); Faculty of Health Sciences, Simon Fraser University, Canada (I.T.); Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (F.T., P.N., M.R.W.); Centre for Molecular Medicine and Therapeutics and Child and Family Research Institute, University of British Columbia, Canada (L.-H.Z., M.K., M.R.H.); Department of Pediatrics, University Medical Center Groningen, University of Groningen, The Netherlands (L.G.D., U.J.F.T.); Xenon Pharmaceuticals, Burnaby, Canada (I.T., C.R.); Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore (C.H.T., V.A.); Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Austria (F.D., J.B.); Beaulieu-Saucier Université de Montréal Pharmacogenomics Centre, Canada (A.B., M.-P.D.); Montréal Heart Institute Research Centre, Canada (A.B., M.-P.D.); and Université de Montréal, Canada (A.B., M.-P.D.).
Lidiya G. Dimova
From the Translational Laboratory in Genetic Medicine, A*STAR Institute, and Yong Loo Lin School of Medicine, National University of Singapore (L.T.-M., D.C., E.C.C., L.J.T., D.H.W., G.K.Y., M.R.H., R.R.S.); Departments of Vascular Medicine and Experimental Vascular Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands (J.C.v.C., A.W.M.S., G.M.D.-T., G.K.H.); Faculty of Health Sciences, Simon Fraser University, Canada (I.T.); Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (F.T., P.N., M.R.W.); Centre for Molecular Medicine and Therapeutics and Child and Family Research Institute, University of British Columbia, Canada (L.-H.Z., M.K., M.R.H.); Department of Pediatrics, University Medical Center Groningen, University of Groningen, The Netherlands (L.G.D., U.J.F.T.); Xenon Pharmaceuticals, Burnaby, Canada (I.T., C.R.); Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore (C.H.T., V.A.); Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Austria (F.D., J.B.); Beaulieu-Saucier Université de Montréal Pharmacogenomics Centre, Canada (A.B., M.-P.D.); Montréal Heart Institute Research Centre, Canada (A.B., M.-P.D.); and Université de Montréal, Canada (A.B., M.-P.D.).
Alinda W.M. Schimmel
From the Translational Laboratory in Genetic Medicine, A*STAR Institute, and Yong Loo Lin School of Medicine, National University of Singapore (L.T.-M., D.C., E.C.C., L.J.T., D.H.W., G.K.Y., M.R.H., R.R.S.); Departments of Vascular Medicine and Experimental Vascular Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands (J.C.v.C., A.W.M.S., G.M.D.-T., G.K.H.); Faculty of Health Sciences, Simon Fraser University, Canada (I.T.); Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (F.T., P.N., M.R.W.); Centre for Molecular Medicine and Therapeutics and Child and Family Research Institute, University of British Columbia, Canada (L.-H.Z., M.K., M.R.H.); Department of Pediatrics, University Medical Center Groningen, University of Groningen, The Netherlands (L.G.D., U.J.F.T.); Xenon Pharmaceuticals, Burnaby, Canada (I.T., C.R.); Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore (C.H.T., V.A.); Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Austria (F.D., J.B.); Beaulieu-Saucier Université de Montréal Pharmacogenomics Centre, Canada (A.B., M.-P.D.); Montréal Heart Institute Research Centre, Canada (A.B., M.-P.D.); and Université de Montréal, Canada (A.B., M.-P.D.).
Ian Tietjen
From the Translational Laboratory in Genetic Medicine, A*STAR Institute, and Yong Loo Lin School of Medicine, National University of Singapore (L.T.-M., D.C., E.C.C., L.J.T., D.H.W., G.K.Y., M.R.H., R.R.S.); Departments of Vascular Medicine and Experimental Vascular Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands (J.C.v.C., A.W.M.S., G.M.D.-T., G.K.H.); Faculty of Health Sciences, Simon Fraser University, Canada (I.T.); Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (F.T., P.N., M.R.W.); Centre for Molecular Medicine and Therapeutics and Child and Family Research Institute, University of British Columbia, Canada (L.-H.Z., M.K., M.R.H.); Department of Pediatrics, University Medical Center Groningen, University of Groningen, The Netherlands (L.G.D., U.J.F.T.); Xenon Pharmaceuticals, Burnaby, Canada (I.T., C.R.); Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore (C.H.T., V.A.); Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Austria (F.D., J.B.); Beaulieu-Saucier Université de Montréal Pharmacogenomics Centre, Canada (A.B., M.-P.D.); Montréal Heart Institute Research Centre, Canada (A.B., M.-P.D.); and Université de Montréal, Canada (A.B., M.-P.D.).
Chris Radomski
From the Translational Laboratory in Genetic Medicine, A*STAR Institute, and Yong Loo Lin School of Medicine, National University of Singapore (L.T.-M., D.C., E.C.C., L.J.T., D.H.W., G.K.Y., M.R.H., R.R.S.); Departments of Vascular Medicine and Experimental Vascular Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands (J.C.v.C., A.W.M.S., G.M.D.-T., G.K.H.); Faculty of Health Sciences, Simon Fraser University, Canada (I.T.); Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (F.T., P.N., M.R.W.); Centre for Molecular Medicine and Therapeutics and Child and Family Research Institute, University of British Columbia, Canada (L.-H.Z., M.K., M.R.H.); Department of Pediatrics, University Medical Center Groningen, University of Groningen, The Netherlands (L.G.D., U.J.F.T.); Xenon Pharmaceuticals, Burnaby, Canada (I.T., C.R.); Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore (C.H.T., V.A.); Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Austria (F.D., J.B.); Beaulieu-Saucier Université de Montréal Pharmacogenomics Centre, Canada (A.B., M.-P.D.); Montréal Heart Institute Research Centre, Canada (A.B., M.-P.D.); and Université de Montréal, Canada (A.B., M.-P.D.).
Liang Juin Tan
From the Translational Laboratory in Genetic Medicine, A*STAR Institute, and Yong Loo Lin School of Medicine, National University of Singapore (L.T.-M., D.C., E.C.C., L.J.T., D.H.W., G.K.Y., M.R.H., R.R.S.); Departments of Vascular Medicine and Experimental Vascular Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands (J.C.v.C., A.W.M.S., G.M.D.-T., G.K.H.); Faculty of Health Sciences, Simon Fraser University, Canada (I.T.); Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (F.T., P.N., M.R.W.); Centre for Molecular Medicine and Therapeutics and Child and Family Research Institute, University of British Columbia, Canada (L.-H.Z., M.K., M.R.H.); Department of Pediatrics, University Medical Center Groningen, University of Groningen, The Netherlands (L.G.D., U.J.F.T.); Xenon Pharmaceuticals, Burnaby, Canada (I.T., C.R.); Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore (C.H.T., V.A.); Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Austria (F.D., J.B.); Beaulieu-Saucier Université de Montréal Pharmacogenomics Centre, Canada (A.B., M.-P.D.); Montréal Heart Institute Research Centre, Canada (A.B., M.-P.D.); and Université de Montréal, Canada (A.B., M.-P.D.).
Chung Hwee Thiam
From the Translational Laboratory in Genetic Medicine, A*STAR Institute, and Yong Loo Lin School of Medicine, National University of Singapore (L.T.-M., D.C., E.C.C., L.J.T., D.H.W., G.K.Y., M.R.H., R.R.S.); Departments of Vascular Medicine and Experimental Vascular Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands (J.C.v.C., A.W.M.S., G.M.D.-T., G.K.H.); Faculty of Health Sciences, Simon Fraser University, Canada (I.T.); Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (F.T., P.N., M.R.W.); Centre for Molecular Medicine and Therapeutics and Child and Family Research Institute, University of British Columbia, Canada (L.-H.Z., M.K., M.R.H.); Department of Pediatrics, University Medical Center Groningen, University of Groningen, The Netherlands (L.G.D., U.J.F.T.); Xenon Pharmaceuticals, Burnaby, Canada (I.T., C.R.); Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore (C.H.T., V.A.); Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Austria (F.D., J.B.); Beaulieu-Saucier Université de Montréal Pharmacogenomics Centre, Canada (A.B., M.-P.D.); Montréal Heart Institute Research Centre, Canada (A.B., M.-P.D.); and Université de Montréal, Canada (A.B., M.-P.D.).
Pradeep Narayanaswamy
From the Translational Laboratory in Genetic Medicine, A*STAR Institute, and Yong Loo Lin School of Medicine, National University of Singapore (L.T.-M., D.C., E.C.C., L.J.T., D.H.W., G.K.Y., M.R.H., R.R.S.); Departments of Vascular Medicine and Experimental Vascular Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands (J.C.v.C., A.W.M.S., G.M.D.-T., G.K.H.); Faculty of Health Sciences, Simon Fraser University, Canada (I.T.); Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (F.T., P.N., M.R.W.); Centre for Molecular Medicine and Therapeutics and Child and Family Research Institute, University of British Columbia, Canada (L.-H.Z., M.K., M.R.H.); Department of Pediatrics, University Medical Center Groningen, University of Groningen, The Netherlands (L.G.D., U.J.F.T.); Xenon Pharmaceuticals, Burnaby, Canada (I.T., C.R.); Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore (C.H.T., V.A.); Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Austria (F.D., J.B.); Beaulieu-Saucier Université de Montréal Pharmacogenomics Centre, Canada (A.B., M.-P.D.); Montréal Heart Institute Research Centre, Canada (A.B., M.-P.D.); and Université de Montréal, Canada (A.B., M.-P.D.).
Daniel Heqing Wu
From the Translational Laboratory in Genetic Medicine, A*STAR Institute, and Yong Loo Lin School of Medicine, National University of Singapore (L.T.-M., D.C., E.C.C., L.J.T., D.H.W., G.K.Y., M.R.H., R.R.S.); Departments of Vascular Medicine and Experimental Vascular Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands (J.C.v.C., A.W.M.S., G.M.D.-T., G.K.H.); Faculty of Health Sciences, Simon Fraser University, Canada (I.T.); Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (F.T., P.N., M.R.W.); Centre for Molecular Medicine and Therapeutics and Child and Family Research Institute, University of British Columbia, Canada (L.-H.Z., M.K., M.R.H.); Department of Pediatrics, University Medical Center Groningen, University of Groningen, The Netherlands (L.G.D., U.J.F.T.); Xenon Pharmaceuticals, Burnaby, Canada (I.T., C.R.); Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore (C.H.T., V.A.); Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Austria (F.D., J.B.); Beaulieu-Saucier Université de Montréal Pharmacogenomics Centre, Canada (A.B., M.-P.D.); Montréal Heart Institute Research Centre, Canada (A.B., M.-P.D.); and Université de Montréal, Canada (A.B., M.-P.D.).
Fabian Dorninger
From the Translational Laboratory in Genetic Medicine, A*STAR Institute, and Yong Loo Lin School of Medicine, National University of Singapore (L.T.-M., D.C., E.C.C., L.J.T., D.H.W., G.K.Y., M.R.H., R.R.S.); Departments of Vascular Medicine and Experimental Vascular Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands (J.C.v.C., A.W.M.S., G.M.D.-T., G.K.H.); Faculty of Health Sciences, Simon Fraser University, Canada (I.T.); Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (F.T., P.N., M.R.W.); Centre for Molecular Medicine and Therapeutics and Child and Family Research Institute, University of British Columbia, Canada (L.-H.Z., M.K., M.R.H.); Department of Pediatrics, University Medical Center Groningen, University of Groningen, The Netherlands (L.G.D., U.J.F.T.); Xenon Pharmaceuticals, Burnaby, Canada (I.T., C.R.); Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore (C.H.T., V.A.); Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Austria (F.D., J.B.); Beaulieu-Saucier Université de Montréal Pharmacogenomics Centre, Canada (A.B., M.-P.D.); Montréal Heart Institute Research Centre, Canada (A.B., M.-P.D.); and Université de Montréal, Canada (A.B., M.-P.D.).
Gopala Krishna Yakala
From the Translational Laboratory in Genetic Medicine, A*STAR Institute, and Yong Loo Lin School of Medicine, National University of Singapore (L.T.-M., D.C., E.C.C., L.J.T., D.H.W., G.K.Y., M.R.H., R.R.S.); Departments of Vascular Medicine and Experimental Vascular Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands (J.C.v.C., A.W.M.S., G.M.D.-T., G.K.H.); Faculty of Health Sciences, Simon Fraser University, Canada (I.T.); Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (F.T., P.N., M.R.W.); Centre for Molecular Medicine and Therapeutics and Child and Family Research Institute, University of British Columbia, Canada (L.-H.Z., M.K., M.R.H.); Department of Pediatrics, University Medical Center Groningen, University of Groningen, The Netherlands (L.G.D., U.J.F.T.); Xenon Pharmaceuticals, Burnaby, Canada (I.T., C.R.); Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore (C.H.T., V.A.); Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Austria (F.D., J.B.); Beaulieu-Saucier Université de Montréal Pharmacogenomics Centre, Canada (A.B., M.-P.D.); Montréal Heart Institute Research Centre, Canada (A.B., M.-P.D.); and Université de Montréal, Canada (A.B., M.-P.D.).
Amina Barhdadi
From the Translational Laboratory in Genetic Medicine, A*STAR Institute, and Yong Loo Lin School of Medicine, National University of Singapore (L.T.-M., D.C., E.C.C., L.J.T., D.H.W., G.K.Y., M.R.H., R.R.S.); Departments of Vascular Medicine and Experimental Vascular Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands (J.C.v.C., A.W.M.S., G.M.D.-T., G.K.H.); Faculty of Health Sciences, Simon Fraser University, Canada (I.T.); Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (F.T., P.N., M.R.W.); Centre for Molecular Medicine and Therapeutics and Child and Family Research Institute, University of British Columbia, Canada (L.-H.Z., M.K., M.R.H.); Department of Pediatrics, University Medical Center Groningen, University of Groningen, The Netherlands (L.G.D., U.J.F.T.); Xenon Pharmaceuticals, Burnaby, Canada (I.T., C.R.); Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore (C.H.T., V.A.); Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Austria (F.D., J.B.); Beaulieu-Saucier Université de Montréal Pharmacogenomics Centre, Canada (A.B., M.-P.D.); Montréal Heart Institute Research Centre, Canada (A.B., M.-P.D.); and Université de Montréal, Canada (A.B., M.-P.D.).
Veronique Angeli
From the Translational Laboratory in Genetic Medicine, A*STAR Institute, and Yong Loo Lin School of Medicine, National University of Singapore (L.T.-M., D.C., E.C.C., L.J.T., D.H.W., G.K.Y., M.R.H., R.R.S.); Departments of Vascular Medicine and Experimental Vascular Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands (J.C.v.C., A.W.M.S., G.M.D.-T., G.K.H.); Faculty of Health Sciences, Simon Fraser University, Canada (I.T.); Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (F.T., P.N., M.R.W.); Centre for Molecular Medicine and Therapeutics and Child and Family Research Institute, University of British Columbia, Canada (L.-H.Z., M.K., M.R.H.); Department of Pediatrics, University Medical Center Groningen, University of Groningen, The Netherlands (L.G.D., U.J.F.T.); Xenon Pharmaceuticals, Burnaby, Canada (I.T., C.R.); Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore (C.H.T., V.A.); Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Austria (F.D., J.B.); Beaulieu-Saucier Université de Montréal Pharmacogenomics Centre, Canada (A.B., M.-P.D.); Montréal Heart Institute Research Centre, Canada (A.B., M.-P.D.); and Université de Montréal, Canada (A.B., M.-P.D.).
Marie-Pierre Dubé
From the Translational Laboratory in Genetic Medicine, A*STAR Institute, and Yong Loo Lin School of Medicine, National University of Singapore (L.T.-M., D.C., E.C.C., L.J.T., D.H.W., G.K.Y., M.R.H., R.R.S.); Departments of Vascular Medicine and Experimental Vascular Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands (J.C.v.C., A.W.M.S., G.M.D.-T., G.K.H.); Faculty of Health Sciences, Simon Fraser University, Canada (I.T.); Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (F.T., P.N., M.R.W.); Centre for Molecular Medicine and Therapeutics and Child and Family Research Institute, University of British Columbia, Canada (L.-H.Z., M.K., M.R.H.); Department of Pediatrics, University Medical Center Groningen, University of Groningen, The Netherlands (L.G.D., U.J.F.T.); Xenon Pharmaceuticals, Burnaby, Canada (I.T., C.R.); Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore (C.H.T., V.A.); Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Austria (F.D., J.B.); Beaulieu-Saucier Université de Montréal Pharmacogenomics Centre, Canada (A.B., M.-P.D.); Montréal Heart Institute Research Centre, Canada (A.B., M.-P.D.); and Université de Montréal, Canada (A.B., M.-P.D.).
Johannes Berger
From the Translational Laboratory in Genetic Medicine, A*STAR Institute, and Yong Loo Lin School of Medicine, National University of Singapore (L.T.-M., D.C., E.C.C., L.J.T., D.H.W., G.K.Y., M.R.H., R.R.S.); Departments of Vascular Medicine and Experimental Vascular Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands (J.C.v.C., A.W.M.S., G.M.D.-T., G.K.H.); Faculty of Health Sciences, Simon Fraser University, Canada (I.T.); Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (F.T., P.N., M.R.W.); Centre for Molecular Medicine and Therapeutics and Child and Family Research Institute, University of British Columbia, Canada (L.-H.Z., M.K., M.R.H.); Department of Pediatrics, University Medical Center Groningen, University of Groningen, The Netherlands (L.G.D., U.J.F.T.); Xenon Pharmaceuticals, Burnaby, Canada (I.T., C.R.); Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore (C.H.T., V.A.); Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Austria (F.D., J.B.); Beaulieu-Saucier Université de Montréal Pharmacogenomics Centre, Canada (A.B., M.-P.D.); Montréal Heart Institute Research Centre, Canada (A.B., M.-P.D.); and Université de Montréal, Canada (A.B., M.-P.D.).
Geesje M. Dallinga-Thie
From the Translational Laboratory in Genetic Medicine, A*STAR Institute, and Yong Loo Lin School of Medicine, National University of Singapore (L.T.-M., D.C., E.C.C., L.J.T., D.H.W., G.K.Y., M.R.H., R.R.S.); Departments of Vascular Medicine and Experimental Vascular Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands (J.C.v.C., A.W.M.S., G.M.D.-T., G.K.H.); Faculty of Health Sciences, Simon Fraser University, Canada (I.T.); Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (F.T., P.N., M.R.W.); Centre for Molecular Medicine and Therapeutics and Child and Family Research Institute, University of British Columbia, Canada (L.-H.Z., M.K., M.R.H.); Department of Pediatrics, University Medical Center Groningen, University of Groningen, The Netherlands (L.G.D., U.J.F.T.); Xenon Pharmaceuticals, Burnaby, Canada (I.T., C.R.); Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore (C.H.T., V.A.); Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Austria (F.D., J.B.); Beaulieu-Saucier Université de Montréal Pharmacogenomics Centre, Canada (A.B., M.-P.D.); Montréal Heart Institute Research Centre, Canada (A.B., M.-P.D.); and Université de Montréal, Canada (A.B., M.-P.D.).
Uwe J.F. Tietge
From the Translational Laboratory in Genetic Medicine, A*STAR Institute, and Yong Loo Lin School of Medicine, National University of Singapore (L.T.-M., D.C., E.C.C., L.J.T., D.H.W., G.K.Y., M.R.H., R.R.S.); Departments of Vascular Medicine and Experimental Vascular Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands (J.C.v.C., A.W.M.S., G.M.D.-T., G.K.H.); Faculty of Health Sciences, Simon Fraser University, Canada (I.T.); Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (F.T., P.N., M.R.W.); Centre for Molecular Medicine and Therapeutics and Child and Family Research Institute, University of British Columbia, Canada (L.-H.Z., M.K., M.R.H.); Department of Pediatrics, University Medical Center Groningen, University of Groningen, The Netherlands (L.G.D., U.J.F.T.); Xenon Pharmaceuticals, Burnaby, Canada (I.T., C.R.); Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore (C.H.T., V.A.); Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Austria (F.D., J.B.); Beaulieu-Saucier Université de Montréal Pharmacogenomics Centre, Canada (A.B., M.-P.D.); Montréal Heart Institute Research Centre, Canada (A.B., M.-P.D.); and Université de Montréal, Canada (A.B., M.-P.D.).
Markus R. Wenk
From the Translational Laboratory in Genetic Medicine, A*STAR Institute, and Yong Loo Lin School of Medicine, National University of Singapore (L.T.-M., D.C., E.C.C., L.J.T., D.H.W., G.K.Y., M.R.H., R.R.S.); Departments of Vascular Medicine and Experimental Vascular Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands (J.C.v.C., A.W.M.S., G.M.D.-T., G.K.H.); Faculty of Health Sciences, Simon Fraser University, Canada (I.T.); Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (F.T., P.N., M.R.W.); Centre for Molecular Medicine and Therapeutics and Child and Family Research Institute, University of British Columbia, Canada (L.-H.Z., M.K., M.R.H.); Department of Pediatrics, University Medical Center Groningen, University of Groningen, The Netherlands (L.G.D., U.J.F.T.); Xenon Pharmaceuticals, Burnaby, Canada (I.T., C.R.); Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore (C.H.T., V.A.); Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Austria (F.D., J.B.); Beaulieu-Saucier Université de Montréal Pharmacogenomics Centre, Canada (A.B., M.-P.D.); Montréal Heart Institute Research Centre, Canada (A.B., M.-P.D.); and Université de Montréal, Canada (A.B., M.-P.D.).
Michael R. Hayden
From the Translational Laboratory in Genetic Medicine, A*STAR Institute, and Yong Loo Lin School of Medicine, National University of Singapore (L.T.-M., D.C., E.C.C., L.J.T., D.H.W., G.K.Y., M.R.H., R.R.S.); Departments of Vascular Medicine and Experimental Vascular Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands (J.C.v.C., A.W.M.S., G.M.D.-T., G.K.H.); Faculty of Health Sciences, Simon Fraser University, Canada (I.T.); Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (F.T., P.N., M.R.W.); Centre for Molecular Medicine and Therapeutics and Child and Family Research Institute, University of British Columbia, Canada (L.-H.Z., M.K., M.R.H.); Department of Pediatrics, University Medical Center Groningen, University of Groningen, The Netherlands (L.G.D., U.J.F.T.); Xenon Pharmaceuticals, Burnaby, Canada (I.T., C.R.); Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore (C.H.T., V.A.); Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Austria (F.D., J.B.); Beaulieu-Saucier Université de Montréal Pharmacogenomics Centre, Canada (A.B., M.-P.D.); Montréal Heart Institute Research Centre, Canada (A.B., M.-P.D.); and Université de Montréal, Canada (A.B., M.-P.D.).
G. Kees Hovingh
From the Translational Laboratory in Genetic Medicine, A*STAR Institute, and Yong Loo Lin School of Medicine, National University of Singapore (L.T.-M., D.C., E.C.C., L.J.T., D.H.W., G.K.Y., M.R.H., R.R.S.); Departments of Vascular Medicine and Experimental Vascular Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands (J.C.v.C., A.W.M.S., G.M.D.-T., G.K.H.); Faculty of Health Sciences, Simon Fraser University, Canada (I.T.); Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (F.T., P.N., M.R.W.); Centre for Molecular Medicine and Therapeutics and Child and Family Research Institute, University of British Columbia, Canada (L.-H.Z., M.K., M.R.H.); Department of Pediatrics, University Medical Center Groningen, University of Groningen, The Netherlands (L.G.D., U.J.F.T.); Xenon Pharmaceuticals, Burnaby, Canada (I.T., C.R.); Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore (C.H.T., V.A.); Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Austria (F.D., J.B.); Beaulieu-Saucier Université de Montréal Pharmacogenomics Centre, Canada (A.B., M.-P.D.); Montréal Heart Institute Research Centre, Canada (A.B., M.-P.D.); and Université de Montréal, Canada (A.B., M.-P.D.).
Roshni R. Singaraja
From the Translational Laboratory in Genetic Medicine, A*STAR Institute, and Yong Loo Lin School of Medicine, National University of Singapore (L.T.-M., D.C., E.C.C., L.J.T., D.H.W., G.K.Y., M.R.H., R.R.S.); Departments of Vascular Medicine and Experimental Vascular Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands (J.C.v.C., A.W.M.S., G.M.D.-T., G.K.H.); Faculty of Health Sciences, Simon Fraser University, Canada (I.T.); Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (F.T., P.N., M.R.W.); Centre for Molecular Medicine and Therapeutics and Child and Family Research Institute, University of British Columbia, Canada (L.-H.Z., M.K., M.R.H.); Department of Pediatrics, University Medical Center Groningen, University of Groningen, The Netherlands (L.G.D., U.J.F.T.); Xenon Pharmaceuticals, Burnaby, Canada (I.T., C.R.); Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore (C.H.T., V.A.); Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Austria (F.D., J.B.); Beaulieu-Saucier Université de Montréal Pharmacogenomics Centre, Canada (A.B., M.-P.D.); Montréal Heart Institute Research Centre, Canada (A.B., M.-P.D.); and Université de Montréal, Canada (A.B., M.-P.D.).

Notes

The online-only Data Supplement is available with this article at http://atvb.ahajournals.org/lookup/suppl/doi:10.1161/ATVBAHA.117.309574/-/DC1.
Correspondence to Roshni R. Singaraja, PhD, National University of Singapore, 8A Biomedical Grove, Singapore 138648, Singapore. E-mail [email protected].

Disclosures

C. Radomski is an employee and M.R. Hayden is on the board at Xenon Pharmaceuticals.

Sources of Funding

Funding was provided by Xenon Pharmaceuticals (Burnaby, BC, Canada), Merck (Rahway, New Jersey), the Agency for Science, Technology and Research (A*STAR, Singapore), and the National University of Singapore (to M. R. Hayden and R. R. Singaraja), as well as by the CardioVascular Research Initiative (CVON2011-19; Genius) and the European Union (Resolve: FP7-305707 and TransCard: FP7-603091–2) (to G. K. Hovingh), and the Austrian Science Fund (I 2738-B26) (to J. Berger). G. K. Hovingh is a holder of a Vidi grant (016.156.445) from the Netherlands Organisation for Scientific Research (Nederlandse Organisatie voor Wetenschappelijk Onderzoek). M. R. Wenk and F. Torta were supported by grants from the National University of Singapore via the Life Sciences Institute (LSI), the National Research Foundation (NRFI2015-05), and a BMRC-SERC joint grant (BMRC-SERC 112 148 0006) from the Agency for Science, Technology and Research (A*STAR).

Metrics & Citations

Metrics

Citations

Download Citations

If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Select your manager software from the list below and click Download.

  1. Identification of Transcripts with Shared Roles in the Pathogenesis of Postmenopausal Osteoporosis and Cardiovascular Disease, International Journal of Molecular Sciences, 25, 10, (5554), (2024).https://doi.org/10.3390/ijms25105554
    Crossref
  2. Bioinformatics and Experimental Study Revealed LINC00982/ miR-183-5p/ABCA8 Axis Suppresses LUAD Progression, Current Cancer Drug Targets, 24, 6, (654-667), (2024).https://doi.org/10.2174/0115680096266700231107071222
    Crossref
  3. Tumour suppressor ABCA8 inhibits malignant progression of colorectal cancer via Wnt/β-catenin pathway, Digestive and Liver Disease, 56, 5, (880-893), (2024).https://doi.org/10.1016/j.dld.2023.10.026
    Crossref
  4. Differential Expression of ABC Transporter Genes in Brain Vessels vs. Peripheral Tissues and Vessels from Human, Mouse and Rat, Pharmaceutics, 15, 5, (1563), (2023).https://doi.org/10.3390/pharmaceutics15051563
    Crossref
  5. Cardiac PET Imaging of ATP Binding Cassette (ABC) Transporters: Opportunities and Challenges, Pharmaceuticals, 16, 12, (1715), (2023).https://doi.org/10.3390/ph16121715
    Crossref
  6. Down-Regulation of ABCA7 in Human Microglia, Astrocyte and THP-1 Cell Lines by Cholesterol Depletion, IL-1β and TNFα, or PMA, Cells, 12, 17, (2143), (2023).https://doi.org/10.3390/cells12172143
    Crossref
  7. Identification of the diagnostic genes and immune cell infiltration characteristics of gastric cancer using bioinformatics analysis and machine learning, Frontiers in Genetics, 13, (2023).https://doi.org/10.3389/fgene.2022.1067524
    Crossref
  8. Proteomic analysis of diabetic retinas, Frontiers in Endocrinology, 14, (2023).https://doi.org/10.3389/fendo.2023.1229089
    Crossref
  9. Analysis of differentially expressed genes related to cerebral ischaemia in young rats based on the Gene Expression Omnibus database, World Journal of Clinical Cases, 11, 7, (1467-1476), (2023).https://doi.org/10.12998/wjcc.v11.i7.1467
    Crossref
  10. ABCA9 , an ER cholesterol transporter, inhibits breast cancer cell proliferation via SREBP ‐2 signaling , Cancer Science, 114, 4, (1451-1463), (2023).https://doi.org/10.1111/cas.15710
    Crossref
  11. See more
Loading...

View Options

View options

PDF and All Supplements

Download PDF and All Supplements

PDF/ePub

View PDF/ePub

Get Access

Login options

Check if you have access through your login credentials or your institution to get full access on this article.

Personal login Institutional Login
Purchase Options

Purchase this article to access the full text.

Purchase access to this article for 24 hours

ABCA8 Regulates Cholesterol Efflux and High-Density Lipoprotein Cholesterol Levels
Arteriosclerosis, Thrombosis, and Vascular Biology
  • Vol. 37
  • No. 11

Purchase access to this journal for 24 hours

Arteriosclerosis, Thrombosis, and Vascular Biology
  • Vol. 37
  • No. 11
Restore your content access

Enter your email address to restore your content access:

Note: This functionality works only for purchases done as a guest. If you already have an account, log in to access the content to which you are entitled.

Media

Figures

Other

Tables

Share

Share

Share article link

Share

Comment Response