Abstract
Hypercholesterolemia is characterized by elevated plasma levels of LDL in which the cholesteryl ester (CE)-rich LDL subclasses of light and intermediate density (LDL1+2 and LDL3, respectively) typically predominate. The molecular mechanisms implicated in oxidation of LDL particle subclasses in hypercholesterolemia are indeterminate. Lipid hydroperoxides (LOOH), primary oxidation products in LDL, are implicated in atherogenesis. LOOH formation was evaluated in light (LDL1+2), intermediate (LDL3), and dense (LDL4+5) LDL subclasses from hypercholesterolemic (HC) subjects (n = 7) during copper-mediated oxidative stress, and compared with that in corresponding subclasses from normolipidemic subjects (n = 7). HC LDL subclasses were distinguished by lower polyunsaturated phospholipid-α-tocopherol ratios (P < 0.02), lower contents of phosphatidyl choline (PC)16:0-18:0/18:2 and PC16:0-18:0/20:4+22:6 (P < 0.002), and higher surface phospholipid-free cholesterol ratios (P < 0.04). The LDL3, LDL4, and LDL5 subclasses in HC subjects displayed low-core polyunsaturated CE-α-tocopherol ratios (P < 0.05), despite similar PUFA CE content. These physicochemical differences did not modify the oxidative susceptibility of HC LDL but underlie the marked instability of cholesterol linoleate hydroperoxides in HC LDL1+2, LDL3, and LDL4 subclasses. Elevated concentrations of large, CE-rich, light, and intermediate LDL subclasses (LDL1+2, LDL3) in hypercholesterolemia may therefore act as an abundant proatherogenic source of highly unstable LOOH in the arterial wall.—Chancharme, L., P. Thérond, F. Nigon, S. Zarev, A. Mallet, E. Bruckert, and M. J. Chapman. LDL particle subclasses in hypercholesterolemia: molecular determinants of reduced lipid hydroperoxide stability. J. Lipid Res. 2002. 43: 453–462.
Highlights
Hypercholesterolemia is characterized by elevated plasma levels of LDL in which the cholesteryl ester (CE)-rich LDL subclasses of light and intermediate density (LDL1؉2 and LDL3, respectively) typically predominate
The LDL profiles are characterized by a predominance of the intermediate LDL3 subclass in each case, which represented approximately 40% of total lipoprotein mass in both HC and NL subjects
Molecular analysis of physicochemically defined subclasses of LDL particles at progressive stages of coppermediated oxidation has revealed a markedly diminished stability of CE-derived hydroperoxides in LDL subspecies from HC patients. This phenomenon was highly significant in CE-rich light LDL1ϩ2 (CE-apoB ratio ϭ 1,900 mol/mol), in the CE-rich intermediate LDL subclass (LDL3; CE-apoB ratio ϭ 1,800 mol/mol), and in CE-poor small, dense LDL4 (CE-apoB ratio ϭ 1,350 mol/mol), and was centered on hydroperoxides of cholesteryl linoleate (Fig. 3), similar instability was seen in CEOOH20:4, which did not attain significance
Summary
Hypercholesterolemia is characterized by elevated plasma levels of LDL in which the cholesteryl ester (CE)-rich LDL subclasses of light and intermediate density (LDL1؉2 and LDL3, respectively) typically predominate. In primary hypercholesterolemia of type IIA, the elevated plasma concentrations of both light, large LDL (LDL1ϩ2), and LDL of intermediate density (LDL3) frequently predominate relative to those of small, dense LDL (LDL4ϩ5) [7, 8]. In this context, it is relevant that available evidence substantiates the elevated atherogenic potential of small, dense LDL, and of large, cholesterol-rich LDL particles.
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