ABCA1 mutation carriers with low high-density lipoprotein cholesterol are characterized by a larger atherosclerotic burden

Abstract

Carriers of loss of function ABCA1 mutations display a larger atherosclerotic burden compared with age and sex-matched controls, implying a higher risk for CVD. Further studies are needed to elucidate the full function of ABCA1 in the protection against atherosclerosis. These data support the development of strategies to up-regulate ABCA1 in patients with established CVD.

ATP-Binding Cassette Transporters, Atherosclerosis, and Inflammation

“…102 This is supported by a study in ABCA1 heterozygotes in which there was an inverse correlation between cholesterol efflux and carotid atherosclerotic plaque burden as assessed by carotid intima-media thickness. 103 A recent study showed increased atherosclerosis in ABCA1 heterozygotes as assessed by carotid MRI, 101 which is a more specific method for measuring atherosclerotic plaque burden than carotid intimamedia thickness, 104 thus further corroborating the increased atherosclerosis in ABCA1 heterozygotes.…”

“…107 It must be noted, however, that only small decreases in HDL, of ≈28% as opposed to ≈50% in previously reported ABCA1 heterozygotes, were observed. 94,[101][102][103]107 Also, the residual cholesterol efflux was substantial (74%-79% for P1065S and G1216V and 48%-49% for N1800H and R2144X for homozygous mutations compared with controls), 107 whereas in patients with TD there was only 20% to 30% residual cholesterol efflux. 108 In addition, LDL levels were reduced by ≈25%, probably offsetting the effects of reduced HDL on CVD.…”

“…100 In heterozygous ABCA1 carriers, either increased CVD or no CVD phenotype has been reported. 94,[101][102][103] It has been suggested that the lack of CVD phenotype in some heterozygotes is attributable to a higher level of residual cholesterol efflux compared with the heterozygotes with increased CVD. 102 This is supported by a study in ABCA1 heterozygotes in which there was an inverse correlation between cholesterol efflux and carotid atherosclerotic plaque burden as assessed by carotid intima-media thickness.…”

Effect of open-label infusion of an apoA-I-containing particle (CER-001) on RCT and artery wall thickness in patients with FHA

“…apoA-I has been shown to play a key role in the initial step of reverse cholesterol transport (RCT) ( 7,8 ). Tissue cholesterol effl ux was decreased in patients with the orphan disease of genetically-determined low HDL-c, familial hypoalphalipoproteinemia (FHA) ( 9 ), which coincided with accelerated atherogenesis ( 10,11 ). Early results from infusion experiments with reconstituted HDL corroborated a therapeutic potential, showing increased fecal cholesterol excretion ( 12,13 ), as well as a reduction in the cholesterol content in human atherosclerotic lesions ( 14 ).…”

Paraoxonase 1‐treated oxLDL promotes cholesterol efflux from macrophages by stimulating the PPARγ–LXRα–ABCA1 pathway

“…It promotes cellular cholesterol efflux and maintains cellular cholesterol homeostasis [17]. A mutation of ABCA1 has been shown to abolish cholesterol efflux and increase the risk of developing atherosclerosis [18]. ABCA1 is regulated both at the transcriptional level via liver X receptor (LXR)/retinoid X receptor-mediated induction of the ABCA1 gene [19] and at the post-translational level via changes in the turnover of the ABCA1 protein [20].…”