Effect of glycation of high density lipoproteins on their physicochemical properties and on paraoxonase activity

Abstract

We investigated the effect of incubation of high density lipoprotein (HDL) under hyperglycaemic conditions on lipid composition, physicochemical properties and activity of paraoxonase (PON), a calcium-dependent enzyme associated with HDL that contributes to the antiatherogenicity of this lipoprotein. HDL incubated for three days with various glucose concentrations (0-100 mM) had significant increases in thiobarbituric acid-reactive substances (TBARS) and conjugated dienes with respect to control HDL. These results suggest that lipid peroxidation accompanies HDL glycation in vitro. The susceptibility to lipid peroxidation was higher in HDL isolated from subjects with low HDL-paraxonase activity with respect to subjects with higher HDL-PON activity. The lipid compositional changes were associated with modifications of apoprotein conformation as shown by the red-shifted position of the maximum emission of tryptophan in treated HDL. The decrease in the Gp (generalized polarization) value and the red-shifted position of the maximum emission of Laurdan incorporated in treated HDL demonstrate modifications of order and polarity with respect to control HDL. The negative correlation established between the Gp value and TBARS demonstrates that the modifications in molecular order are likely related to the increase in lipid peroxidation products. The activity of paraoxonase was significantly decreased in HDL incubated at 37 degrees C; a greater decrease occurred in the presence of 50 mM and 100 mM glucose. This study demonstrates modifications of lipid composition, apoprotein conformation and physicochemical properties of HDL incubated in the presence of glucose. These modifications affect the activity of HDL-associated paraoxonase. The physicochemical properties of lipoproteins play a regulatory role in lipoprotein function. The modification of order and polarity of glycated HDL and the alterations in paraoxonase activity could potentially contribute to the accelerated atherosclerosis in diabetic patients.

HDL‐paraoxonase and Membrane Lipid Peroxidation: A Comparison Between Healthy and Obese Subjects

“…The individual values of PON1 activity associated to HDL showed a large variability in agreement with our previous studies (3,9,14,15). PON1 activity values in HDL isolated from healthy subjects ranged from 110.2 to 980.1 U/mg and from 26.1 to 276.2 U/mg in obese subjects.…”

“…Moreover, previous studies have shown a relationship between PON1 activity and the HDL antioxidant properties (11,12), and it has been demonstrated that HDL with low PON1 activity behave as atherogenic and proinflammatory particles (13). More recently, it has been demonstrated that PON1 activity modulates the susceptibility of HDL to atherogenic modifications induced in vitro such as glycation and homocysteinylation (14,15). Furthermore, using macrophages, it has been demonstrated that PON1 exerts a modulatory role of cholesterol efflux (16), and it has been suggested that PON1 could modulate the interaction between HDL and biological membranes.…”

Oligomeric States of the Detergent-solubilized Human Serum Paraoxonase (PON1)

“…A practical consequence of this is that formulation of HuPON1 for a use as therapeutics in OP poisoning should include adequate concentration of biocompatible amphiphilic compounds that will preserve the enzyme stability on storage and activity in vivo. In addition, the low specific activity of HuPON1 in serum associated with certain pathologies, such as that reported for diabetes (53)(54)(55), might in fact be due to changes in HDL size and/or shape, which affect the binding affinity and, as a result, stability of the HuPON1 enzyme activity.…”

Evaluation of serum paraoxonase level and dyslipidemia in psoriasis

“…21,22 Multiple risk factors of CVD like hypertension, obesity, diabetes mellitus including abnormal lipids and lipoprotein profile have been associated with psoriasis. Dyslipidemia seems to be related to the severity of psoriasis as it occurs more frequently in patients presenting with large areas of body affected with lesions.…”