Clinical study
Enhanced oxidative susceptibility and reduced antioxidant content of metabolic precursors of small, dense low-density lipoproteins

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Abstract

PURPOSE: Elevated plasma concentrations of low-density lipoproteins (LDL) increase risk for coronary heart disease. However, lipoprotein profiles rich in small, dense LDL particles confer greater risk than those that mainly consist of large, buoyant LDL. This may be due, in part, to the greater oxidative susceptibility of small, dense LDL. In the current studies, we tested whether differences in the oxidative behavior of buoyant and dense LDL arise from differences in their immediate metabolic precursors, intermediate-density lipoproteins.

SUBJECTS AND METHODS: We compared the properties of intermediate-density lipoproteins and buoyant and dense LDL subfractions in 9 subjects with the large, buoyant LDL phenotype versus 6 with the small, dense LDL phenotype. Oxidative susceptibility was evaluated based on conjugated diene formation and parinaric acid oxidation induced by copper. Antioxidants (ubiquinol-10 and α-tocopherol) were measured by high-performance liquid chromatography.

RESULTS: Oxidative susceptibility was increased and antioxidant concentrations were decreased with increasing lipoprotein density (intermediate intermediate-density lipoproteins to buoyant LDL to dense LDL). Intermediate-density lipoproteins from subjects with the small, dense LDL phenotype had a greater oxidative susceptibility (by the parinaric acid test) and lower antioxidant concentrations than corresponding particles from subjects with the large, buoyant LDL phenotype.

CONCLUSIONS: Differences in oxidative susceptibility between large, buoyant and small, dense LDL particles are apparent in their lipoprotein precursors. These results suggest that lipoprotein oxidative susceptibility may be metabolically programmed and that intermediate-density lipoproteins may contribute to the increased risk associated with the small, dense LDL phenotype.

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Subjects

We studied 15 healthy normolipidemic adult volunteers, 9 with the large, buoyant LDL phenotype and 6 with the small, dense LDL phenotype, as determined by nondenaturing gradient gel electrophoresis and analytical ultracentrifugation of plasma (22). We excluded subjects with a plasma triglyceride concentration greater than 250 mg/dL, a plasma total cholesterol concentration greater than 250 mg/dL, or those who used dietary supplements or drugs known to alter plasma lipid or lipoprotein. Subjects

Oxidation properties of lipoprotein subfractions

In both groups of subjects (those with either the large, buoyant or the small, dense LDL phenotype), oxidative susceptibility increased significantly from intermediate-density lipoproteins to buoyant LDL to dense LDL particles Figure 1, Figure 2. Oxidative susceptibility as determined by the parinaric acid test was greater in intermediate-density lipoproteins from subjects with the small, dense LDL versus the large, buoyant LDL phenotype (Figure 2).

Antioxidant content and chemical composition of lipoprotein subfractions

As shown in Figure 3, antioxidant

Discussion

Small, dense LDL particles are more susceptible to oxidation than large, buoyant LDL particles (9–18). This property has been proposed to contribute to the increased disease risk associated with the dense LDL phenotype. In this study, we sought to determine whether these differences in oxidative susceptibility are related to differences in the oxidation properties of the presumed intermediate-density lipoprotein precursors of large, buoyant and small, dense LDL. We tested this hypothesis by

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This research was supported by NIH grants DK02456, HL 30086 and HL 54606 and by the US Department of Energy under contract no. DE-AC03–76SF00098. Dr. Rizzo was the recipient of grants from the Italian Council of Research (Consiglio Nazionale delle Ricerche), Rome, Italy, and from the International Atherosclerosis Society, Houston, Texas.

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