Reverse Cholesterol Transport—A Review of the Process and Its Clinical Implications

OBJECTIVES: This review article will summarize the current knowledge surrounding the reverse cholesterol transport system; the process, the effect of mutations in genes coding for proteins which function in the system, and the possible clinical implications of these alterations. RESULTS: High-density lipoprotein-cholesterol (HDL-C) concentration is a marker for the reverse cholesterol transport (RCT) system, whereby cholesterol is returned from peripheral cells to the liver for reuse or excretion in the bile. Increased HDL-C concentrations are generally accepted to be protective against the future development of atherosclerosis and coronary artery disease (CAD), but recent evidence has indicated that the underlying cause of the increased HDL-C may affect whether it is protective or detrimental. The major steps in the RCT pathway are the efflux of free cholesterol from cells and binding by pre-beta HDL, esterification of HDL-bound cholesterol by lecithin cholesterol acyl transferase (LCAT), cholesteryl ester transfer protein (CETP) mediated exchange of cholesteryl ester and triglycerides between HDL and apo B-containing particles, and hepatic lipase (HL) mediated uptake of cholesterol and triglycerides by the liver. Mutations in proteins active in the RCT pathway can shed light on the functions and control of the various steps in the system. LCAT deficiency, leading to greatly reduced HDL and fish eye disease, is not usually associated with increased risk of CAD. Several new mutations in LCAT have recently been reported, however, which do result in CAD. Mutations leading to reduced CETP activity result in less CE being directed into apo-B containing particles and more remaining in the HDL. This has been associated with increased HDL-C concentrations. The generally accepted hypothesis that reduced CETP activity leads to reduced CAD risk has been challenged by a number of recent publications, and has become an area of active investigation. Mutations leading to reduced HL activity are rare occurrences. To date, all have been associated with increased HDL-C concentrations and CAD. CONCLUSION: The development of techniques to identify and characterize the functional significance of mutations in proteins involved in RCT will aid in the understanding of the mechanisms and control of this pathway.