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J. Biol. Chem., Vol. 275, Issue 46, 35807-35813, November 17, 2000

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Macrophage Colony-stimulating Factor Rapidly Enhances -Migrating Very Low Density Lipoprotein Metabolism in Macrophages through Activation of a G_i/o Protein Signaling Pathway^*

Stewart C. Whitman^§, Alan Daugherty, and Steven R. Post^¶

From the  Division of Cardiovascular Medicine and ^¶ Department of Pharmacology, Atherosclerosis Research Group, Linda and Jack Gill Heart Institute, University of Kentucky, Lexington, Kentucky 40536-0284

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 -migrating very low density lipoproteins (-VLDL) stimulated cholesteryl [³H]oleate deposition. In parallel, M-CSF treatment increased the association and degradation of ¹²⁵I-labeled LDL or -VLDL without altering the amount of lipoprotein bound to the cell surface. The increase in LDL and -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 -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 -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 -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.

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