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ORIGINAL RESEARCH ARTICLE

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

Kelly V. Batt^*, Michael Avella^*, Elizabeth H. Moore^*, Brian Jackson, Keith E. Suckling and Kathleen M. Botham^*,1

^* Department of Veterinary Basic Sciences, The Royal Veterinary College, London NW1 0TU, England; and GlaxoSmithKline, Medicines Research Centre, Stevenage, Herts SG1 2NY, England

To whom requests for reprints should be addressed at ¹ Department of Veterinary Basic Sciences, The Royal Veterinary College, Royal College St., London NW1 0TU, England. E-mail: kbotham{at}rvc.ac.uk

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 [³H]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.

Key Words: chylomicron remnants • low-density lipoprotein • cholesterol • triacylglycerol • oxidized lipoproteins • human macrophages

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