Lipid Oxidation in Carriers of Lecithin:Cholesterol Acyltransferase Gene Mutations

Abstract

Objective Lecithin:cholesterol acyltransferase (LCAT) has been shown to play a role in the depletion of lipid oxidation products, but this has so far not been studied in humans. In this study, we investigated processes and parameters relevant to lipid oxidation in carriers of functional LCAT mutations. Methods and Results In 4 carriers of 2 mutant LCAT alleles, 63 heterozygotes, and 63 family controls, we measured activities of LCAT, paraoxonase 1, and platelet-activating factor-acetylhydrolase; levels of lysophosphatidylcholine molecular species, arachidonic and linoleic acids, and their oxidized derivatives; immunodetectable oxidized phospholipids on apolipoprotein (apo) B–containing and apo(a)-containing lipoproteins; IgM and IgG autoantibodies to malondialdehyde-low-density lipoprotein and IgG and IgM apoB-immune complexes; and the antioxidant capacity of high-density lipoprotein (HDL). In individuals with LCAT mutations, plasma LCAT activity, HDL cholesterol, apoA-I, arachidonic acid, and its oxidized derivatives, oxidized phospholipids on apo(a)-containing lipoproteins, HDL-associated platelet-activating factor-acetylhydrolase activity, and the antioxidative capacity of HDL were gene-dose–dependently decreased. Oxidized phospholipids on apoB-containing lipoproteins was increased in heterozygotes (17%; P<0.001) but not in carriers of 2 defective LCAT alleles. Conclusion Carriers of LCAT mutations present with significant reductions in LCAT activity, HDL cholesterol, apoA-I, platelet-activating factor-acetylhydrolase activity, and antioxidative potential of HDL, but this is not associated with parameters of increased lipid peroxidation; we did not observe significant changes in the oxidation products of arachidonic acid and linoleic acid, immunoreactive oxidized phospholipids on apo(a)-containing lipoproteins, and IgM and IgG autoantibodies against malondialdehyde-low-density lipoprotein. These data indicate that plasma LCAT activity, HDL-associated platelet-activating factor-acetylhydrolase activity, and HDL cholesterol may not influence the levels of plasma lipid oxidation products.

High density lipoproteins and endothelial functions: mechanistic insights and alterations in cardiovascular disease

“…Circulating levels of PAF-AH is also shown to be an independent marker of the risk of CAD ( 81 ). However, in a recent study by Holleboom et al ( 82 ), reduced LCAT activity and PAF-AH activity due to LCAT mutations was not associated with increased plasma lipid peroxidation.…”

Antioxidative activity of high-density lipoprotein (HDL): Mechanistic insights into potential clinical benefit

“…Furthermore, LCAT can work as a chain-breaking antioxidant via its Cys residues at the positions 31 and 184 [109] . There is evidence that mutations in LCAT may reduce antioxidative capacity of HDL [110] . However, these mutations were not associated with increased concentrations of lipid peroxidation products in plasma [110] .…”

Antioxidant properties of HDL

“…Similarly, there is currently limited evidence to support a role for LCAT in the antioxidative activity of HDL (Holleboom et al, 2012 ), but its association with HDL and, like PON1 and PLA2, its role in generating lysophospholipids, does contribute to the hypothesis that HDL provides a safe place to release lysolipids otherwise potentially damaging to cell membranes and other lipoproteins.…”