Indications that paraoxonase-1 contributes to plasma high density lipoprotein levels in familial hypercholesterolemia

Thomas M Van Himbergen,Eugène H.J.M Jansen,Jacqueline De Graaf,Anton F.H Stalenhoef,Hiroaki Hattori,Hieronymus A.M Voorbij,Mark Roest,John J.P Kastelein,Lambertus J.H Van Tits

doi:10.1194/jlr.m400052-jlr200

Abstract

HDL-associated paraoxonase type 1 (PON1) can protect LDL and HDL against oxidative modification in vitro and therefore may protect against cardiovascular disease. We investigated the effects of PON1 levels, activity, and genetic variation on high density lipoprotein-cholesterol (HDL-C) levels, circulating oxidized LDL (OxLDL), subclinical inflammation [high-sensitive C-reactive protein (Hs-CRP)], and carotid atherosclerosis. PON1 genotypes (L55M, Q192R, -107C/T, -162A/G, -824G/A, and -907G/C) were determined in 302 patients with familial hypercholesterolemia. PON1 activity was monitored by the hydrolysis rate of paraoxon, diazoxon, and phenyl acetate. PON1 levels, OxLDL, and Hs-CRP were determined using an immunoassay. The genetic variants of PON1 that were associated with high levels and activity of the enzyme were associated with higher HDL-C levels (P values for trend: 0.008, 0.020, 0.042, and 0.037 for L55M, Q192R, -107C/T, and -907G/C, respectively). In addition to the PON1 genotype, there was also a positive correlation between PON1 levels and activity and HDL-C (PON1 levels: r = 0.37, P < 0.001; paraoxonase activity: r = 0.23, P = 0.01; diazoxonase activity: r = 0.29, P < 0.001; arylesterase activity: r = 0.19, P = 0.03). Our observations support the hypothesis that both PON1 levels and activity preserve HDL-C in plasma.

Highlights

Supplementary key words atherosclerosis antioxidants polymorphisms enzyme capable of hydrolyzing lipid peroxides in LDL [1]
Our aim was to investigate the influence of paraoxonase type 1 (PON1) genotypes and PON1 levels and activity on high density lipoprotein-cholesterol (HDL-C) levels, circulating oxidized low density lipoprotein (OxLDL), inflammation markers [high-sensitive C-reactive protein (Hs-CRP)], and common carotid artery intima-media thickness (CCA-IMT) in patients with familial hypercholesterolemia (FH)
The average low density lipoprotein-cholesterol (LDL-C) level was higher than 8 mmol/l, which is characteristic for FH

Summary

Introduction

Supplementary key words atherosclerosis antioxidants polymorphisms enzyme capable of hydrolyzing lipid peroxides in LDL [1]. Because oxidized low density lipoprotein (OxLDL) has atherogenic and proinflammatory properties [2], PON1 may protect against atherosclerosis. This hypothesis is supported by observations in PON1-deficient mice, which are more prone to develop atherosclerosis than wild-type mice when fed a high-fat/high-cholesterol diet [3]. Even though the physiological role of PON1 in vivo remains to be clarified, the inhibition of both LDL and HDL oxidation may contribute to protection against CVD. Studying PON1 levels and activity, in conjunction with variation at the gene level, gives a more complete view of the role of PON1 in the development of atherosclerosis

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