Abstract
Small, dense, electronegative low density lipoprotein [LDL(-)] is increased in patients with familial hypercholesterolemia and diabetes, populations at increased risk for coronary artery disease. It is present to a lesser extent in normolipidemic subjects. The mechanistic link between small, dense LDL(-) and atherogenesis is not known. To begin to address this, we studied the composition and dynamics of small, dense LDL(-) from normolipidemic subjects. NEFA levels, which correlate with triglyceride content, are quantitatively linked to LDL electronegativity. Oxidized LDL is not specific to small, dense LDL(-) or lipoprotein [a] (i.e., abnormal lipoprotein). Apolipoprotein C-III is excluded from the most abundant LDL (i.e., that of intermediate density: 1.034 < d < 1.050 g/ml) but associated with both small and large LDL(-). In contrast, lipoprotein-associated phospholipase A(2) (LpPLA(2)) is highly enriched only in small, dense LDL(-). The association of LpPLA(2) with LDL may occur through amphipathic helical domains that are displaced from the LDL surface by contraction of the neutral lipid core.
Highlights
Small, dense, electronegative low density lipoprotein [LDL[2]] is increased in patients with familial hypercholesterolemia and diabetes, populations at increased risk for coronary artery disease
LDL subfractionation according to density LDL isolated by density gradient ultracentrifugation was collected into seven fractions that were analyzed for charge, composition, and lipid transfer dynamics (Fig. 1)
NEFA and LDL electronegativity The biology and chemistry of LDL[2] have been topics of interest since the report of Avogaro, Bittolo-Bon, and Cazzolato [9] in 1988; that early work has been reviewed and richly expanded by Sanchez-Quesada, Benitez, and Ordonez-Llanos [41], who recently summarized the current state of knowledge regarding LDL[2]
Summary
Dense, electronegative low density lipoprotein [LDL[2]] is increased in patients with familial hypercholesterolemia and diabetes, populations at increased risk for coronary artery disease. To begin to address this, we studied the composition and dynamics of small, dense LDL[2] from normolipidemic subjects. Plasma contains several forms of modified LDL, including heterogeneously oxidized LDL [6], glycated LDL from diabetic subjects [7], and desialylated LDL [8] Plasma from both normal and dyslipidemic patients contains electronegative low density lipoprotein [LDL[2]] [9]; there have been few comprehensive studies of LDL[2] in normolipidemic subjects. This article is available online at http://www.jlr.org
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