Lipoprotein cholesterol uptake in bone marrow‐derived murine macrophages

Abstract

Macrophage foam cell formation is thought to be a key step in early atherogenesis. However, despite considerable research into this process, the cellular mechanisms responsible are still unclear. We and others have observed that macrophage uptake from lipoproteins exhibits several characteristics that suggest that scavenger receptor (SR)‐independent pathways make a significant contribution. Here we use primary bone marrow‐derived macrophages (BMMs) from wild‐type and SR‐deficient mice to study mechanisms of macrophage lipoprotein uptake. We demonstrate that BMMs take up cholesterol from HDL, LDL and oxLDL in a SR‐independent manner and that accumulation of cholesterol ether occurs selectively compared to apolipoprotein. We also show that lipoprotein uptake is neither saturable nor markedly reduced by unlabeled competitor, suggesting that a low affinity uptake mechanism plays a major role. Using radiolabeled and fluorescently‐labeled ligands, we show that the uptake of native and modified LDL are dependent on actin polymerization and that excess unlabeled competitor does not reduce this process, supporting the hypothesis that macropinocytosis is a major mechanism for LDL internalization in macrophages. We conclude that selective uptake and macropinocytosis are active sources of cholesterol in macrophages and that these processes may be important in foam cell formation in vivo, especially in the absence of SR activity. Supported by HL65730 and HL086670 (DvdW), NIH.