High-density lipoproteins: multifunctional vanguards of the cardiovascular system

The plasma level of high-density lipoprotein (HDL)-cholesterol is inversely correlated with coronary artery disease, the leading cause of death worldwide. HDL particles are thought to mediate the uptake of peripheral cholesterol and, through exchange of core lipids with other lipoproteins or selective uptake by specific receptors, return this cholesterol to the liver for bile acid secretion or hormone synthesis in steroidogenic tissues. HDL particles also act on vascular processes by modulating vasomotor function, thrombosis, cell-adhesion molecule expression, platelet function, nitric oxide release, endothelial cell apoptosis and proliferation. Many of these effects involve signal transduction pathways and gene transcription. Several genetic disorders of HDLs have been characterized at the molecular level. The study of naturally occurring mutations has considerably enhanced understanding of the role of HDL particles. Some mutations causing HDL deficiency are associated with premature coronary artery disease, while others, paradoxically, may be associated with longevity. Modulation of HDL metabolism for therapeutic purposes must take into account, not only the cholesterol content of a particle but its lipid (especially phospholipid) composition, apolipoprotein content, size and charge. Current therapeutic strategies include the use of peroxisome proliferating activator receptor-alpha agonists (fibrates) that increase apolipoprotein AI production and increase lipoprotein lipase activity, statins that have a small effect on HDL-cholesterol but markedly reduce low-density lipoprotein-cholesterol, the cholesterol/HDL-cholesterol ratio and niacin that increases HDL-cholesterol. Potential therapeutic targets include inhibition of cholesteryl ester transfer protein, modulating the ATP-binding cassette A1 transporter, and decreasing HDL uptake by scavenger receptor-B1. Novel therapies include injection of purified apolipoprotien AI and short peptides taken orally, mimicking some of the biological effects of apolipoprotein AI.