Lipid efflux in human and mouse macrophagic cells: evidence for differential regulation of phospholipid and cholesterol efflux.
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.
Lipoprotein and Atherosclerosis Research Group, University of Ottawa Heart Institute, Ottawa, Ontario, K1Y 4W7, Canada.
Robert S
RS
Kiss
Jovana
J
Maric
Yves L
YL
Marcel
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000502:physiology; D000818:Animals; D000841:Anisomycin / Q000494:pharmacology; D016632:Apolipoprotein A-I / Q000378:metabolism; D002460:Cell Line; D002461:Cell Line, Transformed; D002784:Cholesterol / Q000378:metabolism*; D000242:Cyclic AMP / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000502:physiology; D006706:Homeostasis; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D050356:Lipid Metabolism; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D010455:Peptides / Q000494:pharmacology; D037342:Pertussis Toxin / Q000494:pharmacology; D010743:Phospholipids / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D014862:Wasp Venoms / Q000494:pharmacology
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D010743:Phospholipids; D014862:Wasp Venoms; D000841:Anisomycin; C037500:mastoparan; D002784:Cholesterol; D000242:Cyclic AMP; D037342:Pertussis Toxin; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D019206:GTP-Binding Protein alpha Subunits, Gi-Go