Modification of HDL₃ by mild oxidative stress increases ATP-binding cassette transporter 1-mediated cholesterol efflux

Objective: Elevated levels of high-density lipoprotein (HDL) cholesterol are inversely related to the risk of cardiovascular disease. The anti-atherosclerotic function of HDL is mainly ascribed to its role in reverse cholesterol transport, and requires the integrity of HDL structure. Experimental evidence suggests that the ability of HDL to promote removal of excess cholesterol from peripheral cells is impaired upon oxidation. On the other hand, tyrosylation of HDL enhances its protective function, suggesting that not all forms of modified lipoprotein may be atherogenic. In the present study we investigated the effect of a mild oxidation of HDL₃ on its function as cholesterol acceptor. Methods and results: A mild oxidative stress (induced by 15 min exposure of HDL₃ to 1 μM Cu⁺⁺ or to 15-lipoxygenase) caused the formation of pre-β-migrating particles. Compared to native lipoprotein, mildly modified HDL₃ induced a significant ATP-binding cassette transporter 1 (ABCA1)-mediated increase of cholesterol and phospholipids efflux from J774 macrophages. This effect was abolished by an inhibitor of ABCA1-mediated lipid efflux (glyburide) and was absent in Tangier fibroblasts. Conclusions: A mild oxidative modification of HDL₃ may improve its function as cholesterol acceptor, increasing ABCA1-mediated lipid efflux from macrophages, a process that may reduce foam cell formation.