ENHANCED CHOLESTEROL EFFLUX BY TYROSYL RADICAL-OXIDIZED HIGH-DENSITY-LIPOPROTEIN IS MEDIATED BY APOLIPOPROTEIN AI-AII HETERODIMERS

Myeloperoxidase secreted by phagocytes in the artery wall may be a cat alyst for lipoprotein oxidation, High density lipoprotein (HDL) oxidiz ed by peroxidase-generated tyrosyl radical has a markedly enhanced abi lity to deplete cultured cells of cholesterol, We have investigated th e structural modifications in tyrosylated HDL responsible for this eff ect. Spherical reconstituted HDL (rHDL) containing the whole apolipopr otein (apo) fraction of tyrosylated HDL reproduced the ability of inta ct tyrosylated HDL to enhance cholesterol efflux from cholesterol-load ed human fibroblasts when reconstituted with the whole lipid fraction of either HDL or tyrosylated HDL, Free apoAI or apoAII showed no incre ased capacity to induce cholesterol efflux from cholesterol-loaded fib roblasts following oxidation by tyrosyl radical, either in their lipid -free forms or in rHDL, The product of oxidation of a mixture of apoAI and apoAII (1:1 molar ratio) by tyrosyl radical, however, reproduced the enhanced ability of tyrosylated HDL to induce cholesterol efflux w hen reconstituted with the whole lipid fraction of HDL, HDL containing only apoAI or apoAII showed no enhanced ability to promote cholestero l efflux following oxidation by tyrosyl radical, whereas HDL containin g both apoAI and apoAII did. rHDL containing apoAI-apoAII(monomer) and apoAI-(apoAII)(2) heterodimers showed a markedly increased ability to prevent the accumulation of LDL-derived cholesterol mass by sterol-de pleted fibroblasts compared with other apolipoprotein species of tyros ylated HDL, These results indicate a novel product of HDL oxidation, a poAI-apoAII heterodimers, with a markedly enhanced capacity to deplete cells of the regulatory pool of free cholesterol and total cholestero l mass. The recent observation of tyrosyl radical-oxidized LDL in vivo suggests that a similar modification of HDL would significantly enhan ce its ability to deplete peripheral cells of cholesterol in the first step of reverse cholesterol transport.