Abstract 11408: Hepatic ATP-Binding Cassette Transporter A1 Positively Contributes to Reverse Cholesterol Transport in vivo
Reverse cholesterol transport (RCT) is one of the major mechanisms by which HDL protects against atherosclerosis. ATP-binding cassette transporter A1 (ABCA1) plays essential roles in cholesterol efflux from macrophages and HDL formation. Macrophage ABCA1 reportedly enhances RCT in vivo, thus resulting in antiatherogenesis. In contrast, hepatic overexpression of ABCA1 has been reported to accelerate atherosclerosis in mice, which may raise a question whether hepatic ABCA1 negatively regulates RCT in vivo. The present study was therefore undertaken to elucidate the roles of hepatic ABCA1 on RCT by knockdown or rescue the gene by adenoviral vectors in wild type or ABCA1 knockout mice, respectively. Intravenous injection of recombinant adenoviral vectors encoding for synthetic micro RNA for mouse ABCA1 resulted in marked decrease in ABCA1 expression in liver, but not other organs of C57BL/6 mice. In these mice, serum total cholesterol, HDL cholesterol (HDL-C) and phospholipids levels were dramatically decreased after the injection. We also confirmed that hepatic ABCA1 knockdown resulted in marked reductions in HDL-C and -apolipoprotein A-I levels isolated by fast protein liquid chromatography. Macrophage RCT assay revealed that, in parallel to HDL-C levels, hepatic ABCA1 knockdown decreased plasma and fecal 3H-cholesterol counts compared to controls by 50 and 75%, respectively. Conversely, hepatic ABCA1-rescued ABCA1 knockout mice demonstrated a marked increase in cholesterol and phospholipids in HDL fractions and accordingly increased 3H-cholesterol counts in plasma (2.1 fold) and feces (3.9 fold).In conclusion, the present study demonstrates that hepatic ABCA1 positively contributes RCT in vivo. Therefore, hepatic ABCA1 may be an alternative target to macrophages in treating atherosclerosis.
- © 2011 by American Heart Association, Inc.