Remnant particles and their metabolism

The data described in this chapter demonstrate that the metabolic control of processes responsible for the formation, uptake and clearance of remnant particles is considerably more complex than previously believed. It now appears that several interacting reactions are involved in the process, and evidence is accumulating that defects in any one of these reactions may severely affect the optimal metabolic cascade. Proper exposure of receptor-binding domains in apoE and perhaps apoB-100 molecules is mandatory. Lipoprotein lipase-induced triglyceride hydrolysis is essential and responsible for the formation of remnant particles from secreted triglyceride-rich lipoproteins. The existence of apoE molecules that exhibit normal function is important but perhaps not always essential. Sequestration in the liver through lipoprotein lipase and/or apoE-mediated binding to heparan sulphate ('bridging' effect) appears to play an exceedingly important role during the early phase of the remnant clearance process. The 'bridging' is responsible not only for sequestration in the liver but also for enhanced uptake and lysosomal degradation of the particles. At this stage, association with the remnants of newly secreted, liver-derived apoE molecules may occur and add to the affinity of the particles towards receptors, especially if the new apoE molecules are inserted in a favourable conformational configuration. A role for the hepatic lipase has been suggested but is yet to be proved. Finally, it should be emphasized that remnants are cleared from the plasma predominantly, if not exclusively, following interaction with cellular receptors. Although the LDL receptor avidly internalizes remnant particles and is apparently active in species with a low LDL concentration (e.g. mice and rats), a second specialized and specific receptor or receptors must exist. Whether the LRP is the only remnant receptor or other, as yet unidentified, receptor proteins are also present, remains to be established. Data published in the last few years have begun to elucidate the interactions and consequences of the many reactions and proteins that are involved with the metabolism of remnant lipoproteins. More is to be learned, including the association of remnants in processes that lead to initiation/progression of atherosclerosis.