Mechanisms involved in chylomicron remnant lipid uptake by macrophages.

Although it is clear that chylomicron remnants are atherogenic, events leading to their internalization by macrophages are still debated. The lack of apoE (apolipoprotein E) in CRLPs (chylomicron remnant-like particles) reduces macrophage TAG (triacylglycerol) content by approx. 50%, suggesting that, as well as apoE-mediated endocytic uptake, apoE receptor-independent mechanisms are involved in the induction of foam cells by chylomicron remnants. Evaluation of the radioactivity associated with macrophages after incubation with CRLPs containing radiolabelled lipids suggests that the TAG and cholesterol carried by the particles have different kinetics of internalization. In addition, inhibition-based experiments indicate that cholesteryl ester-selective uptake and the extracellular lipoprotein lipase hydrolysis of TAG contribute to cholesterol and TAG accumulation respectively. Thus plasma TAG and cholesterol carried by remnant particles have to be considered two independent and non-interchangeable risk factors for athero-related diseases. In addition, the interaction between CRLPs and macrophages is modulated by dietary oxidized lipids and other lipophilic components. The presence of oxidized lipids, such as 7beta-hydroxycholesterol and 7-oxocholesterol, the major cholesterol oxidation products found in atherosclerotic lesions, in CRLPs interferes with the mechanisms of their internalization, but does not cause quantitative changes of accumulated lipids, while the presence of the plant carotenoid, lycopene, or the antioxidant drug, probucol, enhances lipid accumulation in macrophages by increasing the rate of uptake of the particles and raising the intracellular synthesis of TAG. In conclusion, several mechanisms contribute to the macrophage uptake of postprandial lipoproteins, however, little is known of the balance and modulation between the different pathways.