ATP-binding cassette transporter A1 and cholesterol trafficking

PURPOSE OF REVIEW: Two hallmarks of cardiovascular disease are the presence of sterol-laden macrophages in the artery wall and reduced plasma HDL levels. A cell membrane protein named ATP-binding cassette transporter A1 (ABCA1) mediates secretion of excess cholesterol from cells into the HDL metabolic pathway. The discovery of ABCA1 in 1999 triggered a deluge of studies conducted to characterize the properties of this important transporter. The present review summarizes the more recent of those studies and evaluates their implications for the role of ABCA1 in cholesterol transport, HDL metabolism, and atherogenesis. RECENT FINDINGS: Cell culture experiments have shown that ABCA1 transports cholesterol, phospholipids, and other lipophilic molecules across the plasma membrane, where they are picked up by apolipoproteins containing little or no lipids, but the mechanisms involved are still unclear. It is now apparent that factors in addition to sterols modulate ABCA1 expression by diverse transcriptional and post-transcriptional processes. Studies in humans and mice with ABCA1 mutations revealed that the relative activity of ABCA1 determines plasma HDL levels and influences susceptibility to cardiovascular disease. Mouse models are beginning to provide insights into the function of ABCA1 in vivo but are also raising new questions regarding the contribution of ABCA1 to total cholesterol flux. SUMMARY: Recent studies underscore the critical role of ABCA1 in clearing excess cholesterol from macrophages and generating HDL particles, implicating ABCA1 as an attractive new therapeutic target for treating cardiovascular disease.