Abstract
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.
Highlights
Previous studies have examined lipoprotein metabolism by macrophages following prolonged exposure (>24 h) to macrophage colony-stimulating factor (M-CSF)
We examined whether acute treatment of macrophages with M-CSF would differ from that of prolonged M-CSF exposure by having a significant affect on the metabolism of -VLDL
Using incorporation of [3H]oleic acid into cholesterol esters as a measure of macrophage-mediated lipoprotein metabolism, we found that acute exposure of peritoneal macrophages to M-CSF (10 –100 ng/ml) significantly enhanced -VLDL-induced cholesterol ester deposition (268.2 Ϯ 12.3 versus 372.2 Ϯ 13.7 nmol/mg of protein/5 h at 100 ng/ml of M-CSF; p Ͻ 0.001, n ϭ 3, Fig. 1)
Summary
M-CSF, macrophage colony-stimulating factor; -VLDL, -very low density lipoprotein; LDL, low density lipoprotein; AcLDL, acetylated low density lipoproteins; SR-A, class A scavenger receptor; DMEM, Dulbecco’s modified Eagle’s medium; FBS, fetal bovine serum; BSA, bovine serum albumin; PI 3-kinase, phosphatidylinositoI 3-kinase. We have shown that enhanced -VLDL metabolism following M-CSF treatment involves activation of a Gi/o protein signaling pathway that regulates LDL receptor-mediated lipoprotein metabolism
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