Differential Effects of Low-Density Lipoprotein and Chylomicron Remnants on Lipid Accumulation in Human Macrophages

Abstract

The effects of low-density lipoprotein (LDL) and chylomicron remnants on lipid accumulation in human monocyte-derived macrophages (HMDMs) and in macrophages derived from the human monocyte cell line THP-1 were compared. The HMDMs or THP-1 macrophages were incubated with LDL, oxidized LDL (oxLDL), chylomicron remnant-like particles (CMR-LPs), or oxidized CMR-LPs (oxCMR-LPs), and the amount and type of lipid accumulated were determined. As expected, the lipid content of both cell types was increased markedly by oxLDL but not LDL, and this was due to a rise in cholesterol, cholesteryl ester (CE), and triacylglycerol (TG) levels. In contrast, both CMR-LPs and oxCMR-LPs caused a considerable increase in cellular lipid in HMDMs and THP-1 macrophages, but in this case there was a greater rise in the TG than in the cholesterol or CE content. Lipid accumulation in response to oxLDL, CMR-LPs, and oxCMR-LPs was prevented by the ACAT inhibitor CI976 in HMDMs but not in THP-1 macrophages, where TG levels remained markedly elevated. The rate of incorporation of [(3)H]oleate into CE and TG in THP-1 macrophages was increased by oxLDL, CMR-LPs, and oxCMR-LPs, but incorporation into TG was increased to a greater extent with CMR-LPs and oxCMR-LPs compared with oxLDL. These results demonstrate that both CMR-LPs and oxCMR-LPs cause lipid accumulation in human macrophages comparable to that seen with oxLDL and that oxidation of the remnant particles does not enhance this effect. They also demonstrate that a greater proportion of the lipid accumulated in response to CMR-LPs compared with oxLDL is TG rather than cholesterol or CE and that this is associated with a higher rate of TG synthesis. This study, therefore, provides further evidence to suggest that chylomicron remnants have a role in foam cell formation that is distinct from that of oxLDL.

The role of lipolysis in mediating the proinflammatory effects of very low density lipoproteins in mouse peritoneal macrophages

“…1, 6). These findings are in agreement with previous reports suggesting that incubation of macrophages with TG-rich chylomicron remnants and VLDL promotes TG and FFA accumulation to a greater extent (32) than CEs, which are known to accumulate upon acetylated and oxidized LDL treatment (9,32).…”

“…TGs in fasting plasma are carried in VLDLs, and these VLDLs have been found within human and experimental atherosclerotic lesions (3,4), providing a rationale to study their direct effects on macrophage functions such as foam cell formation and inflammation. It is well established that VLDL causes the accumulation of TGs and FFAs in macrophages (5)(6)(7)(8)(9). This can occur through three different mechanisms: 1) uptake of intact VLDL particles; 2) uptake of VLDL remnants resulting from lipoprotein lipase-mediated lipolysis; and 3) uptake of FFAs produced by VLDL lipolysis, which can be taken into cells through both passive diffusion and receptor-mediated mechanisms.…”

Separation of cellular nonpolar neutral lipids by normal-phase chromatography and analysis by electrospray ionization mass spectrometry

“…No study has previously reported the effect of Toll-like receptor 4 activation on individual molecular species of CEs and the magnitude of the increase of saturated and monounsaturated CEs. Oxidized LDL has been reported to cause a significant accumulation of CEs in THP-1 macrophages, as measured by the incorporation of [ 3 H]oleate into CEs separated by TLC (35). However, there has been no report of individual molecular species of CE changing during transformation of the THP cell into more foam-like cells.…”

Molecular Biology of Atherosclerosis

“…However, oxidized or acetylated LDL could promote foam cell formation as they were bound by various scavenger receptors that were not downregulated. Unmodified ␤-VLDL was found to induce foam cell formation without the need for further modification (115,214). Since these studies, a number of additional LDL modifications, many without oxidation, have been shown to also suffice for foam cell formation (1727).…”