Oxidation of chylomicron remnant-like particles inhibits their uptake by THP-1 macrophages by apolipoprotein E-dependent processes

Abstract

The influence of the oxidative state of chylomicron remnants (CMR) on the mechanisms of their uptake and induction of lipid accumulation by macrophages derived from the human monocyte cell line, THP-1, during foam cell formation was investigated using chylomicron-remnant-like particles (CRLPs) at 3 different levels of oxidation. The oxidative state of CRLPs was varied by exposure to CuSO4 (oxCRLPs) or incorporation of the antioxidant, probucol (pCRLPs) into the particles. oxCRLPs caused significantly less accumulation of triacylglycerol in the macrophages than CRLPs, and their rate of uptake was lower, while pCRLPs caused more lipid accumulation and were taken up faster. Uptake of all 3 types of particles was inhibited to a similar extent when entry via the low density lipoprotein (LDL) receptor related protein (80–90%), LDL receptor (− 30–40%), CD36 (− 40%) and phagocytosis (− 35–40%) was blocked using lactoferrin, excess LDL, anti-CD36 and cytochalasin D, respectively, but blocking scavenger receptors-A or -B1 using poly inosinic acid or excess HDL had no effect. These findings show that oxidation of CRLPs lowers their rate of uptake and induction of lipid accumulation in macrophages. However, oxidation does not change the main pathways of internalisation of CRLPs into THP-1 macrophages, which occur mainly via the LRP with some contribution from the LDLr, while CD36 and phagocytosis have only a minor role, regardless of the oxidative state of the particles. Thus, the effects of CMR oxidation on foam cell formation contrast sharply with those of LDL oxidation and this may be important in the role of dietary oxidized lipids and antioxidants in modulating atherosclerosis.

Postprandial phase time influences the uptake of TAG from postprandial TAG-rich lipoproteins by THP-1 macrophages

“…4(a)). These findings are in agreement with those of previous work demonstrating a decreased mRNA expression of LDLR after the incubation of THP-1 macrophages with CM remnants ( 14 , 34 ) . It is known that the expression of this receptor is inhibited by the intracellular accumulation of cholesterol due to lipoprotein uptake ( 34 , 35 ) .…”

“…This result, together with the visualisation of the lipid content with Oil Red O staining, suggests that postprandial TRL induce the formation of foam cells in THP-1 cell populations mainly by TAG, rather than cholesterol, accumulation. Although there is a great deal of evidence from studies carried out both in vivo and with THP-1 macrophages to indicate that foam cell formation induced by native or modified LDL is caused by the accumulation of CE ( 31 ) , our findings are consistent with those of extensive previous work showing that CM remnants cause excessive TAG accumulation in human monocyte-derived macrophages as well as in the mouse macrophage cell line J774 and THP-1 macrophages ( 6 , 14 , 17 , 32 , 33 ) .…”

“…Direct phagocytosis has also been proposed as a mechanism for the uptake of TRL by macrophages, although it is thought to play only a minor role ( 13 ) . Evidence from previous experiments with THP-1 macrophages suggests that CM remnants are mainly taken up by LRP and LDLR ( 14 ) . However, the exact mechanisms by which TRL cause lipid accumulation in macrophages are not yet completely defined.…”

Phospholipase A2 Mediates Apolipoprotein-Independent Uptake of Chylomicron Remnant-Like Particles by Human Macrophages

“…The pathways mediating macrophage uptake of chylomicron remnants are apolipoproteinE (apoE)-dependent receptor-mediated processes involving the LDL receptor and the LDL receptor-related protein (LRP) [9–11]. However, several studies have found evidence that chylomicron remnant uptake pathways in these cells may be independent of the LDL receptor [6, 12] and apoE production [6].…”

Disturbed Chylomicron Metabolism in Type 2 Diabetes - A Preventable Cause of Atherosclerosis?

“…The main uptake and internalisation being through the LDL receptor related protein (LRP) and the LDL receptor [97]. GLP-1-like agonists are now being widely used in the treatment of diabetes and have a beneficial effect on glycaemia and also lipidaemia [98]. Xiao et al 2011 [99] have recently shown in healthy men that glucagon acutely regulates hepatic but not intestinal lipoprotein www.intechopen.com metabolism both by decreasing lipoprotein particle production and inhibiting particle clearance.…”