Original Article

Uptake of type IV hypertriglyceridemic VLDL by cultured macrophages is enhanced by interferon-

Correspondence to: Murray W. Huff

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. 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. Pre-incubation of cells with IFN- (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- increased low density lipoprotein (LDL)-induced cellular CE 2-fold compared to LDL alone. IFN- 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--enhanced HTG -VLDL uptake was dependent on LPL and ACAT activities. IFN- significantly increased the binding and degradation of ¹²⁵I-labeled LDL. Binding studies with ¹²⁵I-labeled 2-macroglobulin, a known LDL receptor-related protein (LRP) ligand, and experiments with copper-oxidized LDL indicated that the IFN--enhanced uptake was not due to increased expression of the LRP or scavenger receptors.

Thus, IFN- may promote foam cell formation by accelerating macrophage uptake of native lipoproteins. IFN--stimulated CE accumulation in the presence of HTG -VLDL occurs via a process that requires receptor binding-competent apoE and active LPL. IFN--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-. J. Lipid Res. 1999. 40: 1017–1028.

Supplementary key words: cytokine, lipid deposition, lipoprotein, atherosclerosis, lipoprotein lipase, ACAT, J774A.1

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