Mechanisms of disease: proatherogenic HDL--an evolving field

It is well known that, in large populations, HDL-cholesterol levels are inversely related to the risk of atherosclerotic clinical events; however, in an individual, the predictive value of an HDL-cholesterol level is far from perfect. As a result, other HDL-associated factors have been investigated, including the quality and function of HDL in contradistinction to the level of HDL-cholesterol. Regarding their quality, HDL particles are highly heterogeneous and contain varying levels of antioxidants or pro-oxidants, which results in variation in HDL function. It has been postulated that HDL functions to promote reverse cholesterol transport. Recent studies support this role for HDL but also indicate that HDL is a modulator of systemic inflammation. In the absence of inflammation, HDL has a complement of antioxidant enzymes that work to maintain an anti-inflammatory state. In the presence of systemic inflammation, these antioxidant enzymes can be inactivated and HDL can accumulate oxidized lipids and proteins that make it proinflammatory. Under these conditions the main protein of HDL, apolipoprotein A-I, can be modified by reactive oxygen species. This modification impairs the ability of HDL to promote cholesterol efflux by the ATP-binding cassette transporter A-1 pathway. Animal studies and small-scale human studies suggest that measures of the quality and novel functions of HDL might provide an improved means of identifying subjects at increased risk for atherosclerotic events, compared with the current practice of only measuring HDL-cholesterol levels. The quality and function of HDL are also attractive targets for emerging therapies.