Chapter 5 – Reverse Cholesterol Transport in HDL Metabolism: Relevance to Atherosclerosis Progression and Cardiovascular Diseases

Approximately 50 years ago, the concept of reverse cholesterol transport (RCT), corresponding to the specific movement of cholesterol from peripheral tissues back to the liver for excretion, was developed by coupling two early observations: first, cholesterol molecules can be removed from cells toward circulating high-density lipoprotein (HDL) fraction and second, lecithin-cholesterol acyltransferase mediates cholesterol esterification within plasma lipoproteins, preferentially HDL particles. In most cells, cholesterol homeostasis is finely regulated, but in the macrophage, where processes for cholesterol accumulation are not regulated by cholesterol excess, the existence of the cholesterol efflux process and acceptors is critical. Macrophage is the most important cell in fatty streak formation and evolution to atherosclerotic plaque in the vessel wall. Therefore the concept of RCT from macrophages to the liver for ultimate fecal excretion represents an attractive mechanism to explain the atheroprotective role of HDL. However, despite observational studies indicating an inverse relationship between HDL-cholesterol (HDL-C) levels and cardiovascular risk, recent successive failures of several HDL-C-raising drugs have cast a shadow on the RCT concept and revealed a lack in our understanding of HDL biology. Studies on human genetics highlighted that simply raising HDL-C levels may not be sufficient to confer an efficacious cardioprotection, thus developing the concept of HDL function. It has been demonstrated that the capacity of HDL to mediate cholesterol efflux represents a strong predictor of atherosclerosis progression. Equally, an inverse association between the prevalence of coronary disease and HDL efflux capacity has been observed. However, HDL-mediated efflux was paradoxically associated with an increase in the prospective risk of myocardial infarction, stroke, and death. These conflicting observations together with the failure of HDL-C-raising drugs indicate that it is now important to consider the overall efficacy of the RCT pathway, including not only the initial macrophage cholesterol efflux, but also the return of cholesterol to the liver. In the present review we focus on two critical steps of the RCT pathway, i.e., cellular cholesterol efflux and cholesteryl ester transfer protein-mediated cholesterol redistribution between circulating lipoproteins, and their role in atherosclerosis progression and cardiovascular disease.