MINIMALLY OXIDIZED LDL IS A POTENT INHIBITOR OF LECITHIN-CHOLESTEROL ACYLTRANSFERASE ACTIVITY

The oxidation of low density lipoproteins (LDL) has been implicated in the development of atherosclerosis. As a variety of highly reactive l ipid peroxidation products can transfer from oxidized LDL to HDL, we e valuated the potential deleterious effects of LDL oxidation on HDL-cho lesterol metabolism. To address this issue, we exposed the HDL-contain ing d>1.063 g/ml fraction of human plasma to copper-oxidized LDL and a ssessed lecithin:cholesterol acyltransferase (LCAT) activity and apoli poprotein A-I (apoA-I) structure. To determine whether LCAT was direct ly affected by oxidized LDL, independent of crosslinking of apoA-I, we used an exogenous, [C-14] cholesterol-labeled proteoliposome substrat e to measure plasma LCAT activity. We observed an inhibition of LCAT a ctivity where copper-oxidized LDL possessing only 2.3 +/- 0.1 and 7.4 +/- 1.4 TBARS produced 24 +/- 3% and 47 +/- 10% reductions in [C-14] c holesterol esterification by 1 h, respectively. Copper-oxidized LDL th at had been passed through a GF-5 desalting column, while retaining on ly one-third of its original TBARS, possessed nearly all of its LCAT i nhibitory capacity suggesting that the LCAT inhibitory factor(s) was a lipophilic oxidation product. Analysis of polar lipids isolated from copper-oxidized LDL indicated that phospholipid and sterol fractions e ffectively inhibited LCAT. Copper-oxidized LDL, with as little as 6.3 TBARS, also produced intermolecular crosslinking of apoA-I molecules. Taken together, these data suggest that products of LDL oxidation may adversely affect HDL-cholesterol metabolism by two separate mechanisms : 1) a direct inhibitory effect on LCAT activity and 2) through crossl inking of apoA-I. If occurring in vivo, minimally oxidized LDL may imp air cholesteryl ester formation on HDL thereby limiting the ability of HDL to function to function efficiently in the putative antiatherogen ic reverse cholesterol transport pathway.-Bielicki, J. K., T. M. Forte , and M. R. Mc Call. Minimally oxidized LDL is a potent inhibitor of l ecithin:cholesterol acyltransferase activity.