The HDL hypothesis: does high-density lipoprotein protect from atherosclerosis?

Abstract

There is unequivocal evidence of an inverse association between plasma high-density lipoprotein (HDL) cholesterol concentrations and the risk of cardiovascular disease, a finding that has led to the hypothesis that HDL protects from atherosclerosis. This review details the experimental evidence for this "HDL hypothesis". In vitro studies suggest that HDL has a wide range of anti-atherogenic properties but validation of these functions in humans is absent to date. A significant number of animal studies and clinical trials support an atheroprotective role for HDL; however, most of these findings were obtained in the context of marked changes in other plasma lipids. Finally, genetic studies in humans have not provided convincing evidence that HDL genes modulate cardiovascular risk. Thus, despite a wealth of information on this intriguing lipoprotein, future research remains essential to prove the HDL hypothesis correct.

Fig. 1.

Evidence for the HDL hypothesis. Although epidemiological studies have established a strong negative relationship between HDL cholesterol and cardiovascular disease, there are many variables which affect HDL cholesterol levels as well as cardiovascular disease risk simultaneously; the role of these potential confounders is unclear. On the basis of in vitro experiments, HDL has been credited with many putative atheroprotective qualities, but clinical relevance has not been convincingly proven for any of these properties. Animal models yielded conflicting results for most of the key players in HDL metabolism with respect to their effect on plasma HDL levels and atherosclerosis propensity. Only apoA-I, the primary structural protein of HDL, showed a strong and consistent atheroprotective tendency in overexpression and infusion models. In humans, both high-quality genetic association studies and clinical trials have thus far not provided clear-cut evidence in favor of the hypothesis that HDL protects from atherosclerosis.