New insights into the role of the adenosine triphosphate-binding cassette transporters in high-density lipoprotein metabolism and reverse cholesterol transport.
Four adenosine triphosphate-binding cassette (ABC) transporters-ABCA1, ABCG1, ABCG5, and ABCG8-have been identified and shown to modulate cholesterol and lipoprotein metabolism. Recent analyses of ABCA1 indicate that upregulation of ABCA1 in the liver and macrophages of transgenic mice is associated with increased plasma high-density lipoprotein (HDL) cholesterol levels, increased net flux of cholesterol to the liver, and reduced diet-induced atherosclerosis. In ABCA1 transgenic mice, the enhanced expression of hepatic ABCA1 transporters is associated with increased plasma HDL cholesterol levels, suggesting that the liver plays an important role in the levels of plasma HDL cholesterol. Overexpression of ABCG1 in the liver of mice using recombinant ABCG1 vectors results in decreased plasma HDL levels and indicates that ABCG1 can modulate plasma lipoprotein levels in vivo. The potential importance of ABCG1 in reverse cholesterol transport has not been definitively established. Studies in patients with sitosterolemia have identified 2 major new transporters, ABCG5 and ABCG8, that play a pivotal role in the regulation of intestinal cholesterol, plant, and shellfish absorption. Modulation of the expression of ABCG5 and ABCG8 represents an important new mechanism in the regulation of cholesterol absorption in the intestine. The ABC transporters currently represent excellent targets for the development of new drugs for the treatment of patients with increased risk of premature cardiovascular disease.
Brewer
H Bryan
HB
Molecular Disease Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. bryan@mail.nih.gov
Santamarina-Fojo
Silvia
S
D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000235:genetics; D008076:Cholesterol, HDL / Q000235:genetics* / Q000378:metabolism*; D003324:Coronary Artery Disease / Q000209:etiology / Q000235:genetics* / Q000378:metabolism*; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D012307:Risk Factors
D018528:ATP-Binding Cassette Transporters; D008076:Cholesterol, HDL