Macrophage colony-stimulating factor rapidly enhances beta-migrating very low density lipoprotein metabolism in macrophages through activation of a Gi/o protein signaling pathway.
Previous studies have examined lipoprotein metabolism by macrophages following prolonged exposure (>24 h) to macrophage colony-stimulating factor (M-CSF). Because M-CSF activates several signaling pathways that could rapidly affect lipoprotein metabolism, we examined whether acute exposure of macrophages to M-CSF alters the metabolism of either native or modified lipoproteins. Acute incubation of cultured J774 macrophages and resident mouse peritoneal macrophages with M-CSF markedly enhanced low density lipoproteins (LDL) and beta-migrating very low density lipoproteins (beta-VLDL) stimulated cholesteryl [(3)H]oleate deposition. In parallel, M-CSF treatment increased the association and degradation of (125)I-labeled LDL or beta-VLDL without altering the amount of lipoprotein bound to the cell surface. The increase in LDL and beta-VLDL metabolism did not reflect a generalized effect on lipoprotein endocytosis and metabolism because M-CSF did not alter cholesterol deposition during incubation with acetylated LDL. Moreover, M-CSF did not augment beta-VLDL cholesterol deposition in macrophages from LDL receptor (-/-) mice, indicating that the effect of M-CSF was mediated by the LDL receptor. Incubation of macrophages with pertussis toxin, a specific inhibitor of G(i/o) protein signaling, had no effect on cholesterol deposition during incubation with beta-VLDL alone, but completely blocked the augmented response promoted by M-CSF. In addition, incubation of macrophages with the direct G(i/o) protein activator, mastoparan, mimicked the effect of M-CSF by enhancing cholesterol deposition in cells incubated with beta-VLDL, but not acetylated LDL. In summary, M-CSF rapidly enhances LDL receptor-mediated metabolism of native lipoproteins by macrophages through activation of a G(i/o) protein signaling pathway. Together, these findings describe a novel pathway for regulating lipoprotein metabolism.
Whitman
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Division of Cardiovascular Medicine and Department of Pharmacology, Atherosclerosis Research Group, Linda and Jack Gill Heart Institute, University of Kentucky, Lexington, Kentucky 40536-0284, USA.
Daugherty
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D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D002788:Cholesterol Esters / Q000378:metabolism; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins; D007457:Iodine Radioisotopes; D008077:Lipoproteins, LDL / Q000378:metabolism; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D010455:Peptides; D011485:Protein Binding / Q000187:drug effects; D011817:Rabbits; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D014862:Wasp Venoms / Q000494:pharmacology; D000077191:Wortmannin
D000730:Androstadienes; D002788:Cholesterol Esters; D036341:Intercellular Signaling Peptides and Proteins; D007457:Iodine Radioisotopes; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D010455:Peptides; D011973:Receptors, LDL; D011994:Recombinant Proteins; D014862:Wasp Venoms; C032629:acetyl-LDL; C037500:mastoparan; D016173:Macrophage Colony-Stimulating Factor; D020962:Heterotrimeric GTP-Binding Proteins; D000077191:Wortmannin