HDL atherogenesis and reverse cholesterol transport

A number of epidemiological studies have consistently demonstrated that a low plasma concentration of high-density lipoprotein cholesterol (HDL-C) is an independent risk factor for the development of acute coronary events. Clinical sequelae are generally preceded by silent changes in the arterial wall, characterized by enhanced lipid deposition and infiltration of blood cells into the subendothelial space. Indeed, the low plasma HDL-C levels in subjects with primary hypoalphalipoproteinemia are associated with a significant thickening of the carotid arterial wall, as assessed by measuring the thickness of the intima media complex (IMT) by non-invasive B-mode ultrasonography. Moreover, in a large cohort of hyperlipidemic subjects, a curvilinear relationship exists between plasma HDL-C and carotid thickening, with the greatest influence of HDL-C on IMT being from low to average values. HDL are believed to retard the formation of atherosclerotic lesions in the arterial wall by removing excess cholesterol from cells and transporting it to the liver, in a process known as reverse cholesterol transport (RCT). The first step in RCT is the efflux of cellular cholesterol, which occurs through two mechanisms: i) interaction of lipid-free apolipoproteins with a specific transporter in the cell membrane (ABC1). efflux of phospholipids and cholesterol, and generation of small. pre-beta-HDL; ii) passive diffusion of cholesterol from the cell membrane into HDL acceptors, facilitated by the scavenger receptor BI (SR-BI). Once incorporated into HDL. cholesterol is esterified by the lecithin:cholesterol acyltransferase (LCAT) enzyme. The newly synthesized cholesteryl esters are transferred by the cholesteryl ester transfer protein (CETP) to triglyceride-rich lipoproteins, that transport them to the liver. or are directly delivered by HDL to the liver through interaction with SR-BI. Mutations in the genes encoding for apolipoproteins, enzymes. lipid transfer proteins and receptors involved in RCT cause marked alterations in the plasma levels of HDL, with the accumulation in plasma of either dysfunctional or hyperfunctional HDL. In these opposite conditions. the qualitative rather than quantitative features of the HDL system determine the efficiency of reverse cholesterol transport and the individual coronary risk.