Can Electronegative LDL Act as a Multienzymatic Complex?

Abstract

Electronegative LDL (LDL(-)) is a minor form of LDL present in blood for which proportions are increased in pathologies with increased cardiovascular risk. In vitro studies have shown that LDL(-) presents pro-atherogenic properties, including a high susceptibility to aggregation, the ability to induce inflammation and apoptosis, and increased binding to arterial proteoglycans; however, it also shows some anti-atherogenic properties, which suggest a role in controlling the atherosclerotic process. One of the distinctive features of LDL(-) is that it has enzymatic activities with the ability to degrade different lipids. For example, LDL(-) transports platelet-activating factor acetylhydrolase (PAF-AH), which degrades oxidized phospholipids. In addition, two other enzymatic activities are exhibited by LDL(-). The first is type C phospholipase activity, which degrades both lysophosphatidylcholine (LysoPLC-like activity) and sphingomyelin (SMase-like activity). The second is ceramidase activity (CDase-like). Based on the complementarity of the products and substrates of these different activities, this review speculates on the possibility that LDL(-) may act as a sort of multienzymatic complex in which these enzymatic activities exert a concerted action. We hypothesize that LysoPLC/SMase and CDase activities could be generated by conformational changes in apoB-100 and that both activities occur in proximity to PAF-AH, making it feasible to discern a coordinated action among them.

Keywords: LDL aggregation; ceramidase; electronegative LDL; inflammation; low-density lipoprotein; modified LDL; phospholipase C; platelet-activating factor acetylhydrolase; sphingomyelinase.

Figure 1

Scheme of the putative cooperative actions of PAF-AH, LysoPLC, and CDase activities. Stage 1: The attack of reactive oxygen species (ROS) on phosphatidylcholine favors the appearance of oxidized phospholipids (oxPC) that would act as a substrate for PAF-AH coming from macrophages, yielding LPC and oxNEFA. Stage 2: Minimal oxidation of LDL would promote a conformational change in the N-terminus of apoB (red square) causing the appearance of LysoPLC/SMase-like activity. The action of this enzymatic activity on the SM would produce the formation of Cer. Stage 3: A second conformational change at the C-terminus of apoB (blue square) could favor the appearance of CDase-like activity, which would degrade Cer, forming Sph and NEFA as the final products. Notably, this is just one of the possible cooperation schemes between the different enzymatic activities. With the current experimental information, we do not know if the SMase and CDase activities appear at the C-terminus or the N-terminus, or even if the interaction of both ends is necessary for these activities to emerge. Similarly, the proposed sequence of stages could be different or occur simultaneously.