Macrophage colony-stimulating factor rapidly enhances beta-migrating very low density lipoprotein metabolism in macrophages through activation of a G(i/o) protein signaling pathway

Previous studies have examined lipoprotein metabolism by macrophages follow ing prolonged exposure (>24 h) to macrophage colony-stimulating factor (M-C SF). Because M-CSF activates several, signaling pathways that could rapidly affect lipoprotein metabolism, we examined whether acute exposure of macro phages to M-CSF alters the metabolism of either native or modified lipoprot eins, Acute incubation of cultured J774 macrophages and resident mouse peri toneal macrophages with M-CSF markedly enhanced low density lipoproteins (L DL) and beta -migrating very low density lipoproteins (beta -VLDL) stimulat ed cholesteryl [H-3]oleate deposition. In parallel, M-CSF treatment increas ed the association and degradation of I-125-labeled LDL or beta -VLDL witho ut altering the amount of lipoprotein bound to the cell surface. The increa se in LDL and beta -VLDL metabolism did not reflect a generalized effect on lipoprotein endocytosis and metabolism because M-CSF did not alter cholest erol deposition during incubation with acetylated LDL, Moreover, M-CSF did not augment beta -VLDL cholesterol deposition in macrophages from LDL recep tor (-/-) mice, indicating that the effect of M-CSF was mediated by the LDL receptor. Incubation of macrophages with pertussis toxin, a specific inhib itor of G(i/o) protein signaling, had no effect on cholesterol deposition d uring incubation with beta -VLDL alone, but completely blocked the augmente d response promoted by M-CSF. In addition, incubation of macrophages with t he direct G(i/o) protein activator, mastoparan, mimicked the effect of M-CS F by enhancing cholesterol deposition in cells incubated with beta -VLDL, b ut not acetylated LDL, In summary, M-CSF rapidly enhances LDL receptor-medi ated metabolism of native lipoproteins by macrophages through activation of a G(i/o), protein signaling pathway. Together, these findings describe a n ovel pathway for regulating lipoprotein metabolism.