Oxidized type IV hypertriglyceridemic VLDL-remnants cause greater macrophage cholesteryl ester accumulation than oxidized LDL

We have previously shown that very low density lip- oproteins (VLDL, S f 60-400) from subjects with type IV hyperlipoproteinemia (HTG-VLDL) will induce appreciable cholesteryl ester accumulation in cultured macrophages (J774A.1). The present study examined whether copper- mediated oxidative modification of HTG-VLDL and their remnants would further enhance cholesteryl ester accumu- lation in J774A.1 cells. Incubation with oxidized VLDL- remnants caused the greatest increase in cellular cholesteryl ester concentrations (54-fold) relative to control cells ( P 5 0.001). HTG-VLDL and VLDL-remnants each induced simi- lar increases in cholesteryl ester levels (32.3- and 35.8-fold, respectively; both P 5 0.001), whereas incubation with oxi- dized HTG-VLDL brought about only a 20.6-fold increase in cholesteryl ester concentrations ( P 5 0.014). The in- crease in cellular cholesteryl ester concentrations induced by oxidized VLDL-remnants was significantly higher ( P # 0.04) than that induced by all other lipoproteins tested in- cluding low density lipoprotein (LDL) and oxidized LDL which caused a 6.7- and a 35.1-fold increase ( P # 0.0002 for both), respectively. Unlike HTG-VLDL and to a lesser ex- tent VLDL-remnants, uptake of oxidized VLDL and oxi- dized VLDL-remnants did not require catalytically active, cell secreted lipoprotein lipase. Co-incubation with poly- inosine, which blocks binding to the type I scavenger recep- tor, completely inhibited the cholesteryl ester accumulation induced by oxidized HTG-VLDL, oxidized VLDL-remnants and oxidized LDL ( P # 0.02). We conclude that oxida- tion of VLDL-remnants significantly enhances macrophage cholesteryl ester accumulation compared to either HTG- VLDL, VLDL-remnants, or oxidized LDL. Uptake of oxi- dized VLDL and oxidized VLDL-remnants does not require catalytically active lipoprotein lipase, and involves a recep- tor that can be competed for by polyinosine.— Whitman, S. C., C. G. Sawyez, D. B. Miller, B. M. Wolfe, and M. W. Huff. Oxidized Type IV Hypertriglyceridemic VLDL-remnants cause greater macrophage cholesteryl ester accumulation than oxi- dized LDL. J. Lipid Res. 1998. 39: 1008-1020.