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Papers In Press, published online ahead of print July 1, 2005
J. Lipid Res., doi:10.1194/jlr.M400482-JLR200
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Lipoprotein and Atherosclerosis Research Group, University of Ottawa Heart Institute, Ottawa, Ontario K1Y 4W7
Corresponding Author: ylmarcel{at}ottawaheart.ca
ABCA1 is a critical regulator of lipid efflux from cells, which is highly regulated at the transcriptional and post-translational levels. However, cells from different species and different tissues, and primary vs. 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 (MPM), human THP-1 cells, and human monocyte-derived macrophages (MDM). Cyclic AMP (cAMP) was a potent stimulator of lipid efflux in mouse macrophages, but not in human macrophages. Cholera toxin, a Gs protein stimulator mediating its effect through adenylate cyclase, was as efficient as cAMP in each cell type. Moreover, this cAMP inducible component of efflux from MPM was inhibitable by H89 (a protein kinase A 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, demonstrating altered signaling of cAMP and PKA between macrophages of mouse and human origin. In MPM and THP-1 cells, protein kinase C inhibitors blocked cholesterol efflux but had no effect on phospholipid efflux, demonstrating the separation of regulation of phospholipid efflux and cholesterol efflux in macrophages. We conclude: 1) cAMP regulates lipid efflux predominantly in a PKA dependent fashion; 2) phospholipid and cholesterol effluxes are stimulated by a PKA dependent mechanism, and cholesterol efflux is also modulated by a PKC dependent mechanism in macrophages; 3) mouse and human macrophages exhibit different modes of regulation of lipid efflux.
Revised on June 23, 2005
Accepted on June 27, 2005
Lipid efflux in human and mouse macrophagic cells: evidence for differential regulation of phospholipid and cholesterol efflux
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