Both hepatic and extrahepatic ABCA1 have discrete and essential functions in the maintenance of plasma high-density lipoprotein cholesterol levels in vivo

• Published in: Circulation (New York, N.Y.) N.Y.), 2006-09, Vol.114 (12), p.1301-1309
• Main Authors: SINGARAJA, Roshni R, VAN ECK, Miranda, VAN BERKEL, Theo J. C, PARKS, John S, STAELS, Bart, ROTHBLAT, George H, FIEVET, Catherine, HAYDEN, Michael R, BISSADA, Nagat, ZIMETTI, Francesca, COLLINS, Heidi L, HILDEBRAND, Reeni B, HAYDEN, Anna, BRUNHAM, Liam R, KANG, Martin H, FRUCHART, Jean-Charles
• Format: Article
• Language: English
• Subjects: Adenoviridae; Animals; Apolipoprotein A-I - pharmacology; Atherosclerosis (general aspects, experimental research); ATP Binding Cassette Transporter 1; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; ATP-Binding Cassette Transporters - physiology; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cholesterol, HDL - blood; Cholesterol, HDL - genetics; Coronary heart disease; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Female; Gene Expression Regulation; Heart; Humans; Liver - metabolism; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.106.621433

Extrahepatic tissues have long been considered critical contributors of cholesterol to nascent HDL particles in the reverse cholesterol transport pathway, in which ABCA1 plays the crucial role. Recent studies, however, including both overexpression and deletion of ABCA1 selectively in the liver, have highlighted the primary role of the liver in the maintenance of HDL levels in vivo. The availability of mice with complete deletion of ABCA1 (total knockout [TKO]) and with liver-specific deletion of ABCA1 (LSKO) has enabled us to dissect the discrete roles of hepatic relative to extrahepatic ABCA1 in HDL biogenesis. Delivery of adenoviral ABCA1 resulted in selective expression of physiological levels of ABCA1 in the livers of both LSKO and TKO mice, resulting in increased HDL cholesterol (HDL-C). Expression of ABCA1 in the liver of LSKO mice resulted in plasma HDL-C levels that were similar to those in wild-type mice and significantly above those seen in similarly treated TKO mice. HDL particles from ABCA1-expressing LSKO mice were larger and contained significantly increased cholesterol compared with TKO mice. Infusion of human apolipoprotein A-I/phospholipid reconstituted HDL particles normalized plasma HDL-C levels in LSKO mice but had no effect on HDL-C levels in TKO mice. Although hepatic ABCA1 appears crucial for phospholipid transport, extrahepatic tissues play an important role in cholesterol transfer to nascent HDL particles. These data highlight the discrete and specific roles of both liver and extrahepatic ABCA1 in HDL biogenesis in vivo and indicate that ABCA1 shows lipid cargo selectivity depending on its site of expression.