Genetics and prevention: a new look at high-density lipoprotein cholesterol.

Plasma level of high-density lipoprotein cholesterol is inversely correlated with coronary artery disease. High-density lipoprotein 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. During the past decade, high-density lipoprotein particles have been found to modulate thrombosis, cell adhesion molecule expression, vasomotor function, platelet function, and endothelial cell apoptosis and proliferation. Many of these effects involve the signal transduction pathway and gene transcription. Genetic disorders of high-density lipoproteins have been characterized at the molecular level. Mutations within the genes involved in the structure and metabolism of high-density lipoproteins can cause high-density lipoprotein deficiency or elevations in high-density lipoprotein cholesterol levels. Some mutations causing high-density lipoprotein deficiency are associated with premature coronary artery disease, whereas others, paradoxically, may be associated with longevity. Modulation of high-density lipoprotein metabolism for therapeutic purposes must take into account not only the cholesterol content of the particle but also its lipid (including phospholipid) composition, apolipoprotein content, size, and charge.