Electronegative low-density lipoprotein. A link between apolipoprotein B misfolding, lipoprotein aggregation and proteoglycan binding

Abstract

Subendothelial retention of lipoproteins is considered the first step in the development of atherosclerosis, but the molecular mechanisms involved are poorly understood. Recent findings on the atherogenic properties of a minor electronegative fraction of LDL (LDL(-)) could contribute to a better understanding of this process. Circular dichroism, Trp-fluorescence and two-dimensional nuclear magnetic resonance have shown that apolipoprotein B (apoB) in LDL(-) has an abnormal, misfolded conformation. Immunochemical analysis revealed a different conformation, mainly in the N-terminal and C-terminal extremes. These alterations contribute to the high susceptibility to aggregation of LDL(-). Moreover, LDL(-) can seed the aggregation of native LDL, suggesting an amyloidogenic character that has been attributed to the amphipathic helix cluster in the α2-domain. A phospholipase C (PLC)-like activity associated to LDL(-) seems to play a major role in the LDL(-)-induced aggregation. The aggregation of LDL(-) increases its binding to proteoglycans because of the abnormal conformation of the N-terminal extreme of apoB. LDL(-) could play a relevant role in atherogenesis by acting as a priming factor that stimulates lipoprotein aggregation. This process, which appears to be mediated by a PLC-like activity intrinsic to LDL(-), increases the binding of LDL to proteoglycans and could promote subendothelial retention of these lipoproteins.