Abstract
Hypertriglyceridemic (HTG) very low density lipoproteins (VLDL) from subjects with type IV hyperlipoproteinemia induce both cholesteryl ester (CE) and triglyceride (TG) accumulation in cultured J774 macrophages. We examined whether the cytokine interferon-γ (IFN-γ), which is expressed by lymphocytes in atherosclerotic lesions, would modulate macrophage uptake of HTG-VLDL. Incubation of cells with HTG-VLDL alone significantly increased cellular CE and TG mass 17- and 4.3-fold, respectively, while cellular free cholesterol (FC) was unaffected. Preincubation of cells with IFN-γ (50 U/ml) prior to incubation with HTG-VLDL caused a marked enhancement in cellular CE and TG 27- and 6-fold over no additions (controls), respectively, and a 1.5-fold increase in FC. IFN-γ increased low density lipoprotein (LDL)-induced cellular CE 2-fold compared to LDL alone. IFN-γ did not enhance the uptake of type III (apoE2/E2) HTG-VLDL or VLDL from apoE knock-out mice. Incubations in the presence of a lipoprotein lipase (LPL) inhibitor or an acylCoA:cholesterol acyltransferase (ACAT) inhibitor demonstrated that the IFN-γ-enhanced HTG-VLDL uptake was dependent on LPL and ACAT activities. IFN-γ significantly increased the binding and degradation of 125I-labeled LDL. Binding studies with 125I-labeled α2-macroglobulin, a known LDL receptor-related protein (LRP) ligand, and experiments with copper-oxidized LDL indicated that the IFN-γ-enhanced uptake was not due to increased expression of the LRP or scavenger receptors. Thus, IFN-γ may promote foam cell formation by accelerating macrophage uptake of native lipoproteins. IFN-γ-stimulated CE accumulation in the presence of HTG-VLDL occurs via a process that requires receptor binding-competent apoE and active LPL. IFN-γ-enhanced uptake of both HTG-VLDL and LDL is mediated by the LDL-receptor and requires ACAT-mediated cholesterol esterification.—Whitman, S. C., C. A. Argmann, C. G. Sawyez, D. B. Miller, R. A. Hegele, and M. W. Huff. Uptake of type IV hypertriglyceridemic VLDL by cultured macrophages is enhanced by interferon-γ. J. Lipid Res. 1999. 40: 1017–1028.
Highlights
Hypertriglyceridemic (HTG) very low density lipoproteins (VLDL) from subjects with type IV hyperlipoproteinemia induce both cholesteryl ester (CE) and triglyceride (TG) accumulation in cultured J774 macrophages
The results demonstrated that: 1) IFN-␥ treatment of macrophages resulted in a marked enhancement in cellular CE, free cholesterol (FC), and triglyceride (TG) content upon incubation with native type IV HTG-VLDL; 2) cell-secreted lipoprotein lipase (LPL) was required for this uptake process despite the fact that IFN-␥ treatment reduced cellular LPL activity; 3) IFN-␥-induced CE accumulation required cellular acylCoA:cholesterol acyltransferase (ACAT) activity; and 4) enhanced uptake of HTGVLDL and LDL mediated by IFN-␥ was due to increased uptake via the LDL-receptor and did not involve the LDL receptor-related protein (LRP) or scavenger receptors
Incubation of J774A.1 cells with native type IV HTG -VLDL induced a 17.4-fold and a 4.3-fold increase in cellular CE and TG content, respectively, compared to cells incubated in the absence of lipoproteins
Summary
Hypertriglyceridemic (HTG) very low density lipoproteins (VLDL) from subjects with type IV hyperlipoproteinemia induce both cholesteryl ester (CE) and triglyceride (TG) accumulation in cultured J774 macrophages. We examined whether the cytokine interferon-␥ (IFN-␥), which is expressed by lymphocytes in atherosclerotic lesions, would modulate macrophage uptake of HTG-VLDL. Gupta et al [13] demonstrated that atherosclerosis was significantly attenuated in double knockout mice, created by crossing IFN-␥ receptor knockout mice with EKO mice This suggests a pro- atherogenic role for IFN-␥. In vitro studies have demonstrated that IFN-␥ decreases SR-A, the LDL receptor-related protein (LRP), and lipoprotein lipase (LPL) expression in macrophages and inhibits SMC col-. In vitro studies have focused on the effects of IFN-␥ on macrophage foam cell formation induced by LDL modified by acetylation or oxidation [15, 19]. Despite a major role in regulating macrophage function, little is known about the impact of IFN-␥ on foam cell formation induced by native lipoproteins. Subjects with type IV HLP have elevated levels of VLDL and remnant particles, they often have normal levels of LDL [21, 23], a class of lipoprotein whose elevation is typically associated with atherogenesis [24]
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