Abstract 831: Selective Deficiency of Hepatic ABCA1 Results in Increased Susceptibility to Atherosclerosis
The ATP-binding cassette transporter, sub-family A, member 1 (ABCA1) controls the rate-limiting step in the assembly of high density lipoprotein (HDL) particles, the efflux of cellular cholesterol and phospholipids to an apolipoprotein acceptor. ABCA1 is widely expressed throughout the body, and we have recently demonstrated that hepatic and intestinal ABCA1 are the major contributors to plasma HDL cholesterol levels in vivo. The contributions of ABCA1 in specific tissues to susceptibility to atherosclerosis are less well understood. Mice lacking ABCA1 globally do not develop increased atherosclerosis, possibly due to the concurrent decrease in non-HDL cholesterol observed in these mice. In contrast, bone marrow transplant of either ABCA1 deficient or ABCA1 overexpressing hematopoetic cells does influence atherogenesis, suggesting that macrophage ABCA1 may be an important contributor to atherosclerosis susceptibility. The role of hepatic ABCA1 in atherosclerosis is controversial. To determine the contribution of hepatic ABCA1 to susceptibility to atherosclerosis we assessed the severity of atherosclerosis in mice deficient for hepatic ABCA1 and Apoe compared to mice deficient for Apoe, all on a >95% pure C57Bl6/J genetic background. Mice lacking hepatic ABCA1 had a significant ~30% reduction in total plasma cholesterol. This was associated with approximately 65% greater aortic root lesion area. The increase in atherosclerosis in Apoe deficient mice lacking hepatic ABCA1 was confirmed by a significant increase in aortic total and free cholesterol levels. These data indicate that selective deficiency of hepatic ABCA1 results in increased susceptibility to atherosclerosis, thus suggesting that reduced HDL levels are directly and causally pro-atherogenic in the absence of other alterations in the reverse cholesterol transport pathway. Our data further indicate that therapeutic approaches that directly target hepatic ABCA1, such as though viral gene transfer, are likely to have beneficial effects on atherogenesis in vivo.