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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:1707-1715.)
© 1997 American Heart Association, Inc.

Articles

Uptake of Type III Hypertriglyceridemic VLDL by Macrophages Is Enhanced by Oxidation, Especially After Remnant Formation

Stewart C. Whitman; David B. Miller; Bernard M. Wolfe; Robert A. Hegele; ; Murray W. Huff

From the Departments of Medicine and Biochemistry and the Robarts Research Institute at University of Western Ontario, London, and the Department of Medicine, St Michael's Hospital, University of Toronto (Ont), Canada.

Correspondence to Murray W. Huff, PhD, Robarts Research Institute, 416, University of Western Ontario, London, Ontario, Canada, N6A 5K8. E-mail mhuff{at}julian.uwo.ca

Abstract We previously showed that hypertriglyceridemic VLDL (HTG-VLDL, Sf 60 to 400) from subjects with type III (E2/E2) hyperlipoproteinemia do not induce appreciable cholesteryl ester (CE) accumulation in cultured macrophages (J774A.1). In the present study, we examined whether oxidation of type III HTG-VLDL would enhance their uptake by J774A.1 cells. Type III HTG-VLDL were oxidized as measured by both conjugated-diene formation and increased electrophoretic mobility on agarose gels. Both LDL and type III HTG-VLDL undergo oxidation, albeit under different kinetic parameters. From the conjugated-diene curve, type III HTG-VLDL, compared with LDL, were found to have a 6-fold longer lag time, to take 6-fold longer to reach maximal diene production, and to produce a 2-fold greater amount of dienes but at half the rate (all P<.005). Incubation of macrophages with either native type III HTG-VLDL or LDL (50 µg lipoprotein cholesterol/mL media for 16 hours) caused small increases (4-fold and 2.7-fold, respectively) in cellular CE levels relative to control cells (both P=.0001). After 24 hours of CuSO₄ exposure, we found that oxidized type III HTG-VLDL and LDL caused a 9.4-fold and 10.5-fold increase, respectively, in cellular CE levels (P=.0001). We next examined whether extending the exposure period for type III HTG-VLDL to CuSO₄ beyond 24 hours would further enhance its ability to induce macrophage CE accumulation. After 48 hours of CuSO₄ exposure, type III HTG-VLDL and LDL caused 21.3-fold and 11.6-fold increases, respectively, in cellular CE levels (P=.0001). The cellular CE loading achieved with 48 hour–oxidized type III HTG-VLDL was significantly higher than either 24 hour–oxidized type III HTG-VLDL (2.3-fold, P=.003) or 48 hour–oxidized LDL (1.8-fold, P=.012). There was no significant difference between the CE loading achieved by incubation of cells with either 24 hour–oxidized type III HTG-VLDL, 24 hour–oxidized LDL, or 48 hour–oxidized LDL (P.518). In this study, we also examined whether partial lipolysis (19% to 50% triglyceride hydrolysis) of type III HTG-VLDL to produce remnants would increase the susceptibility of the lipoprotein to oxidative modification and subsequent cellular CE loading. Forty-eight hour–oxidized type III VLDL-remnants stimulated CE accumulation 30.4-fold over baseline (P=.0001). In contrast, nonoxidized type III VLDL-remnants caused the same very low level of CE loading as did native type III HTG-VLDL (P=.680). The increase in cellular CE levels achieved with 48 hour–oxidized type III VLDL-remnants was significantly higher than that achieved with 48 hour–oxidized type III HTG-VLDL (P=.047). In conclusion, we have shown that oxidized type III HTG-VLDL will induce macrophage CE accumulation well above levels achieved with oxidized LDL. In addition, we also showed that by forming a VLDL-remnant before oxidative modification, we can further enhance macrophage CE accumulation. These results provide a potential mechanism for the atherogenicity of type III HTG-VLDL and their remnants.

Key Words: type III HLP • VLDL • remnants • oxidation • foam cells

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