The pathophysiology of excess plasma-free cholesterol

Several large studies have shown increased mortality due to all-causes and to atherosclerotic cardiovascular disease. In most clinical settings, plasma HDL-cholesterol is determined as a sum of free cholesterol and cholesteryl ester, two molecules with vastly different metabolic itineraries. We examine the evidence supporting the concept that the pathological effects of elevations of plasma HDL-cholesterol are due to high levels of the free cholesterol component of HDL-C.

In a small population of humans, a high plasma HDL-cholesterol is associated with increased mortality. Similar observations in the HDL-receptor deficient mouse (Scarb1 -/- ), a preclinical model of elevated HDL-C, suggests that the pathological component of HDL in these patients is an elevated plasma HDL-FC.

Collective consideration of the human and mouse data suggests that clinical trials, especially in the setting of high plasma HDL, should measure free cholesterol and cholesteryl esters and not just total cholesterol.