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Originally published In Press as doi:10.1194/jlr.M400482-JLR200 on July 1, 2005

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Journal of Lipid Research, Vol. 46, 1877-1887, September 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Lipid efflux in human and mouse macrophagic cells: evidence for differential regulation of phospholipid and cholesterol efflux

Robert S. Kiss, Jovana Maric and Yves L. Marcel1

Lipoprotein and Atherosclerosis Research Group, University of Ottawa Heart Institute, and Departments of Pathology and Laboratory Medicine, and Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa Heart Institute, Ottawa, Ontario, K1Y 4W7, Canada

Published, JLR Papers in Press, July 1, 2005. DOI 10.1194/jlr.M400482-JLR200

1 To whom correspondence should be addressed. e-mail: ylmarcel{at}ottawaheart.ca

ABCA1 is a critical regulator of lipid efflux from cells, which is highly regulated at the transcriptional and posttranslational levels. However, cells from different species and different tissues, and primary versus immortalized cells, show different modes of regulation. We have carried out a comparative analysis of basic signaling pathways of lipid efflux in mouse J774 cells, mouse peritoneal macrophages (MPMs), human THP-1 cells, and human monocyte-derived macrophages. Cyclic AMP (cAMP) was a potent stimulator of lipid efflux in mouse macrophages, but not in human macrophages. Moreover, this cAMP-inducible component of efflux from MPMs was inhibitable by H89 [a protein kinase A (PKA) inhibitor], but H89 did not affect basal efflux. On the other hand, cAMP failed to show any stimulatory effect in human macrophages, but basal efflux was inhibitable by H89. In MPMs and THP-1 cells, protein kinase C (PKC) inhibitors blocked cholesterol efflux but had no effect on phospholipid efflux, demonstrating the separation of the regulation of phospholipid efflux and cholesterol efflux in macrophages.

We conclude that: 1) cAMP regulates lipid efflux predominantly in a PKA-dependent fashion; 2) cholesterol efflux is modulated by a PKC-dependent mechanism; and 3) mouse and human macrophages exhibit different modes of regulation of lipid efflux.

Supplementary key words cholesterol efflux • macrophage • ATP binding cassette transporter A1 • lipid efflux • regulation


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