Pivotal role of ABCA1 in reverse cholesterol transport influencing HDL levels and susceptibility to atherosclerosis

The identification of mutations in ABCA1 in patients with Tangier disease a nd familial HDL deficiency demonstrated that inadequate transport of phosph olipid and cholesterol to the extracellular space results in the hypercatab olism of lipid-poor nascent HDL particles. However, the relationship betwee n changes in ABCA1 activity and HDL levels is not clear. To address this qu estion directly in vivo, we have used bacterial artificial chromosome trans genic approaches, which allow for appropriate developmental and cellular lo calization of human ABCA1 in mouse tissues. Increased expression of ABCA1 i s directly associated with an increase in HDL levels, and the relationship between the increase in efflux and HDL is completely linear (r(2) = 0.87). Preliminary data have suggested that coronary artery disease (CAD) is incre ased in heterozygotes for ABCA1 deficiency These results may have been bias ed by clinical sampling, and CAD end points are insensitive markers. We hav e now used surrogate end points of intima-media complex thickness (IMT) and have shown that mean IMT in ABCA1 heterozygotes is indeed increased. A str ong correlation between adjusted IMT and HDL cholesterol values and apolipo protein A-I-driven efflux has been established. These studies suggest that compromised ABCA1 activity leads to accelerated and early atherogenesis and provides a link between the cholesterol deposition in macrophages within t he arterial wall and cholesterol efflux in humans.