Journal of Lipid Research, Vol 36, 322-331, Copyright © 1995 by Lipid Research, Inc.
Copper and gas-phase cigarette smoke inhibit plasma lecithin:cholesterol acyltransferase activity by different mechanisms
JK Bielicki, MR McCall, JJ van den Berg, FA Kuypers and TM Forte
Department of Molecular and Nuclear Medicine, Lawrence Berkeley Laboratory, Berkeley, CA 94720, USA.
Cigarette smokers have reduced levels of plasma high density lipoprotein
(HDL) compared to nonsmokers and are at risk of premature cardiovascular
disease. Previous work from this laboratory has shown that exposure of
human plasma to gas-phase cigarette smoke (CS) inhibited the activity of
lecithin:cholesterol acyltransferase (LCAT), the enzyme that catalyzes the
formation of cholesteryl ester in HDL and thereby promotes HDL maturation.
As CS contains free radicals that could potentially oxidize plasma
lipoproteins, we examined the involvement of lipid peroxidation in LCAT
inhibition. Results obtained with CS were compared with those obtained by
initiating lipid peroxidation with copper ions. Exposure of dialyzed human
plasma to an equivalent of one-eighth of a cigarette at 15-min intervals
resulted in a progressive loss of LCAT activity (50 and 90% reductions by 1
and 6 h, respectively). A similar pattern of LCAT inhibition was produced
with copper (0.5 mM) where 50 and 97% reductions were observed at 1 and 6
h, respectively. To determine whether LCAT inhibition was related to lipid
peroxidation, lipoprotein fractions corresponding to VLDL-IDL, LDL, and HDL
were isolated from plasma exposed to CS or copper and analyzed for changes
in TBARS, the polyunsaturated fatty acid arachidonate relative to palmitate
(20:4/16:0 ratio), and vitamin E concentrations. Exposure of plasma for 6 h
to CS had no effect on the levels of TBARS and 20:4/16:0 ratio; however, 6
h copper treatment (0.5 mM) caused a 3.0-, 4.0-, and 1.4-fold increase in
TBARS and a 17, 25, and 13% reduction in the 20:4/16:0 ratio in VLDL-IDL,
LDL, and HDL fractions, respectively. In addition, a complete depletion of
lipoprotein vitamin E was observed with CS, whereas copper decreased
vitamin E levels by approximately 50% in each fraction. Supplementation of
plasma with either vitamin C (85 microM) or butylated hydroxytoluene (BHT,
0.45 mM) was unable to protect LCAT from CS. In contrast, BHT completely
protected LCAT activity from inhibition by copper. We conclude that unlike
copper, CS-induced inhibition of plasma LCAT activity was unrelated to free
radical-induced lipid peroxidation. The inhibition of LCAT activity by
cigarette smoke may contribute to the development of atherosclerosis by
impairing HDL metabolism and the reverse cholesterol transport process.
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