ABCA1 and atherosclerosis.
ATP binding cassette transporter A1 (ABCA1) mediates the cellular efflux of phospholipids and cholesterol to lipid-poor apolipoprotein A1 (apoA1) and plays a significant role in high density lipoprotein (HDL) metabolism. ABCA1's role in the causation of Tangier disease, characterized by absent HDL and premature atherosclerosis, has implicated this transporter and its regulators liver-X-receptoralpha (LXRalpha) and peroxisome proliferator activated receptorgamma (PPARgamma) as new candidates potentially influencing the progression of atherosclerosis. In addition to lipid regulation, these genes are involved in apoptosis and inflammation, processes thought to be central to atherosclerotic plaque progression. A Medline-based review of the literature was carried out. Tangier disease and human heterozygotes with ABCA1 mutations provide good evidence that ABCA1 is a major candidate influencing atherosclerosis. Animal and in vitro experiments suggest that ABCA1 not only mediates cholesterol and phospholipid efflux, but is also involved in the regulation of apoptosis and inflammation. The complex and beneficial interactions between apoA1 and ABCA1 seem to be pivotal for cholesterol efflux. The expression of the ABCA1 is tightly regulated. Furthermore the plaque microenvironment could potentially promote ABCA1 protein degradation thus compromising cholesterol efflux. PPAR-LXR-ABCA1 interactions are integral to cholesterol homeostasis and these nuclear receptors have proven anti-inflammatory and anti-matrix metalloproteinase activity. Therapeutic manipulation of the ABCA1 transporter is feasible using PPAR and LXR agonists. PPAR agonists like glitazones and ABCA1 protein stabilization could potentially modify the clinical progression of atherosclerotic lesions.
Soumian
S
S
Department of Vascular Surgery, Faculty of Medicine, Imperial College, Charing Cross Hospital, London, UK. s.soumian@imperial.ac.uk
Albrecht
C
C
Davies
A H
AH
Gibbs
R G J
RG
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001161:Arteriosclerosis / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D008076:Cholesterol, HDL / Q000187:drug effects / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D006801:Humans; D008297:Male; D011379:Prognosis; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D013631:Tangier Disease / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics; D045162:Thiazolidinediones / Q000627:therapeutic use*
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D008076:Cholesterol, HDL; D005819:Genetic Markers; D045162:Thiazolidinediones