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 lipid peroxidation products can transfer from oxidized LDL to HDL, we evaluated the potential deleterious effects of LDL oxidation on HDL-cholesterol metabolism. To address this issue, we exposed the HDL-containing d > 1.063 g/ml fraction of human plasma to copperoxidized LDL and assessed lecithin:cholesterol acyltransferase (LCAT) activity and apolipoproteinA-I (apoA-I) structure. To determine whether LCAT was directly affected by oxidized LDL, independent of crosslinking of apoA-I, we used an exogenous, [14C]cholesterol-labeled proteoliposome substrate to measure plasma LCAT activity. We observed an inhibition of LCAT activity where copper-oxidized LDL possessing only 2.3 +/- 0.1 and 7.3 +/- 1.4 TBARS produced 24 +/- 3% and 47 +/- 10% reductions in [14C]cholesterol esterification by 1 h, respectively. Copper-oxidized LDL that had been passed through a GF-5 desalting column, while retaining only one-third of its original TBARS, possessed nearly all of its LCAT inhibitory capacity suggesting that the LCAT inhibitory factor(s) was a lipophilic oxidation product. Analysis of polarlipids isolated from copper-oxidized LDL indicated that phospholipid and sterol fractions effectively 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 crosslinking of apoA-I. If occurring in vivo, minimally oxidized LDL may impair cholesteryl ester formation on HDL thereby limiting the ability of HDL to function efficiently in the putative antiatherogenic reverse cholesterol transport pathway.
Bielicki
J K
JK
Lawrence Berkeley National Laboratory, Life Sciences Division, University of California at Berkeley 94720, USA.
Forte
T M
TM
McCall
M R
MR
D016632:Apolipoprotein A-I / Q000737:chemistry; D005591:Chemical Fractionation; D003300:Copper / Q000378:metabolism; D003432:Cross-Linking Reagents; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D005069:Evaluation Studies as Topic; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000494:pharmacology*; D010084:Oxidation-Reduction; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*
D016632:Apolipoprotein A-I; D003432:Cross-Linking Reagents; D004791:Enzyme Inhibitors; D008077:Lipoproteins, LDL; D003300:Copper; D007862:Phosphatidylcholine-Sterol O-Acyltransferase