ATP-Binding Cassette Transporter A1 in Lipoprotein Metabolism and Atherosclerosis

Abstract

ATP-binding cassette transporter A1 (ABCA1) is a key protein determining high-density lipoprotein (HDL) function. In 1999, it was discovered by 3 independent groups that mutations in the gene for ABCA1 underlie the molecular defect in the HDL deficiency syndrome Tangier disease. Subsequent studies with genetically engineered mice lacking or overexpressing ABCA1 provided evidence that ABCA1 modulates atherosclerosis susceptibility on either end of the reverse cholesterol transport pathway. In the liver (and to a lesser extent in intestine), it determines the biogenesis of nascent HDL particles, whereas in macrophages it is essential for the prevention of the excess cholesterol accumulation by facilitating the transport of cellular cholesterol and phospholipid onto lipid-poor apo AI, the major apoprotein of HDL. See accompanying article on page 2288 Mice lacking ABCA1 in all tissues display a virtual absence of HDL cholesterol (HDL-C) in the circulation.1 This is primarily the consequence of the absence of hepatic ABCA1 as targeted inactivation of ABCA1 in liver resulted in a 83% reduction in the total amount of HDL-C in the circulation.2 Surprisingly, the first studies by Aiello et al3 investigating the effects of ABCA1 deletion in all endogenous tissues failed to show any affect on atherosclerosis susceptibility, neither in the apolipoprotein E knockout (apoE KO) background nor in the low-density lipoprotein receptor knockout (LDLr KO) background. Both models, however, did show marked decreases in proatherogenic apoB lipoproteins on deletion of ABCA1. One could thus also argue that total body ABCA1 KO mice still developed substantial atherosclerosis despite the markedly decreased levels of proatherogenic lipoproteins. Total body KO mice also lack ABCA1 in bone marrow–derived cells, including macrophages that accumulate in the arterial wall during atherosclerotic lesion development. Several bone marrow transplantation studies were performed in LDLr KO and apoE KO mice to investigate the effects of …