MDL-29311, A PHENOLIC ANTIOXIDANT INTERFERES WITH THE INTERACTION OF APOC WITH VLDL - A POSSIBLE EXPLANATION FOR ITS TRIGLYCERIDE-LOWERING EFFECT

MDL 29311 is an antioxidant that lowers plasma triglycerides and raise s high density lipoprotein (HDL) cholesterol in rats. It lowers trigly cerides in rats by enhancing the clearance of very low density lipopro tein (VLDL) by the liver (Sheetz, M. J., et al. 1994. Metabolism. 43: 232-240). In this paper, the possibility that MDL 29311 enhances VLDL clearance by altering the apolipoprotein (apo) content of lipoproteins is examined. Treatment of rats with 1% MDL 29311 in the diet for 7 da ys lowered plasma triglycerides and markedly increased total lipoprote in-associated apoE. The increase in apoE was confined to the HDL fract ion; no increase in VLDL-associated apoE was detected. No apparent alt erations in the amount of total lipoprotein-associated apoC were obser ved, although there was a decrease in VLDL-associated apoC-II and C-II I-0. Consistent with this finding, the amount of I-125-labeled apoC tr ansferred from HDL to VLDL in plasma from MDL 29311-rreated rats was o nly 40% of the amount transferred in control plasma. Sepharose 6B gel filtration of mixtures of I-125-labeled apoC with increasing concentra tions of MDL 29311 in the absence of plasma or lipid revealed that pro portionally increasing amounts of the I-125-labeled apoC eluted in a h igh molecular weight (HMW) complex with MDL 29311. An HMW complex was not formed when MDL 29311 was mixed with I-125-labeled soybean trypsin inhibitor. The I-125-labeled apoC in the HMW complex bound to VLDL on ly 20% as well as uncomplexed I-125-labeled apoC. MDL 29311 also cause d the dissociation of I-125-labeled apoC from VLDL at concentrations o f MDL 29311 similar to those obtained in vivo. Other phenolic antioxid ants related to MDL 29311 caused the formation of HMW I-125-labeled ap oC-containing complexes to an extent proportional to their abilities t o lower triglycerides in rats. These studies support the hypothesis th at MDL 29311 lowers triglycerides in rats by interfering with apoC ass ociation with VLDL, thereby relieving the apoC-mediated inhibition of hepatic VLDL uptake.