Inhibition of Lecithin-Cholesterol Acyltransferase and Modification of HDL Apolipoproteins by Aldehydes

Abstract

Experimental evidence suggests that aldehydes generated as a consequence of lipid peroxidation may be involved in the pathogenesis of atherosclerosis. It is well documented that aldehydes modify LDL: however, less is known concerning the effects of aldehydes on other plasma and interstitial fluid components. In the present study, we investigated the effects of five physiologically relevant aldehydes (acetaldehyde, acrolein, hexanal, 4-hydroxynonenal [HNE], and malondialdehyde [MDA]) on two key constituents of the antiatherogenic reverse cholesterol transport pathway, lecithin-cholesterol acyltransferase (LCAT) and HDL. Human plasma was incubated for 3 hours at 37 degrees C with each one of the five aldehydes at concentrations ranging from 0.16 to 84 mmol/L. Dose-dependent decreases in LCAT activity were observed. The short-chain (acrolein) and long-chain (HNE) alpha,beta-unsaturated aldehydes were the most effective LCAT inhibitors. Micromolar concentrations of these unsaturated aldehydes resulted in significant reductions in plasma LCAT activity. The short- and longer-chain saturated aldehydes acetaldehyde and hexanal and the dialdehyde MDA were considerably less effective at inhibiting LCAT than were acrolein and HNE. In addition to inhibiting LCAT, aldehydes increased HDL electrophoretic mobility and cross-linked HDL apolipoproteins. Cross-linking of apolipoproteins A-I and A-II required higher aldehyde concentrations than inhibition of LCAT. The alpha,beta-unsaturated aldehydes acrolein and HNE were fourfold to eightfold more effective cross-linkers of apolipoproteins A-I and A-II than the other aldehydes studied. These data suggest that products of lipid peroxidation, especially unsaturated aldehydes, may interfere with normal HDL cholesterol transport by inhibiting LCAT and modifying HDL apolipoproteins.

Enhanced Cholesterol Efflux by Tyrosyl Radical-oxidized High Density Lipoprotein Is Mediated by Apolipoprotein AI-AII Heterodimers

“…A pattern of cross-linking of HDL apoproteins like that induced by tyrosyl radical (including apparent apoAI-apoAII heterodimers) is indicated in previous reports using manganese, copper, cigarette smoke, or aldehydes to oxidize HDL particles (51)(52)(53)(54). We have found that incubation of HDL with the crosslinking agent tetranitromethane induces a similar pattern.…”

Decreased Protection by HDL From Poorly Controlled Type 2 Diabetic Subjects Against LDL Oxidation May Be Due to the Abnormal Composition of HDL

“…Aldehydes such as 4-hydroxynonenal and malondialdehyde generated during LDL oxidation can cause apo A-I cross-linking in HDL. 39 Two possible mechanisms for the decreased protection exhibited by HDL 2 from diabetic subjects include the following: (1) The decreased free cholesterol concentration seen in diabetic HDL 2 may alter its surface fluidity, perhaps thereby facilitating the lipid peroxides generated during LDL oxidation to "seed" the HDL 2 . Once seeded with lipid peroxides, the TG-enriched HDL 2 from diabetic subjects may be more susceptible to oxidation and become less protective.…”

Acrolein Impairs ATP Binding Cassette Transporter A1-dependent Cholesterol Export from Cells through Site-specific Modification of Apolipoprotein A-I

“…A variety of reactive aldehydes modify HDL and appear to cross-link its proteins in vitro (30). Modification is associated with loss of the ability of HDL to activate lecithin-cholesterol acyltransferase (30), a key enzyme in reverse cholesterol transport.…”