Journal of Lipid Research, Vol 36, 2609-2621, Copyright © 1995 by Lipid Research, Inc.
MDL 29311, a phenolic antioxidant, interferes with the interaction of apoC with VLDL: a possible explanation for its triglyceride-lowering effect
MJ Sheetz
Marion Merrell Dow Research Institute, Cincinnati, OH 45215, USA.
MDL 29311 is an antioxidant that lowers plasma triglycerides and raises
high density lipoprotein (HDL) cholesterol in rats. It lowers triglycerides
in rats by enhancing the clearance of very low density lipoprotein (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 days lowered plasma triglycerides
and markedly increased total lipoprotein-associated apoE. The increase in
apoE was confined to the HDL fraction; no increase in VLDL-associated apoE
was detected. No apparent alterations in the amount of total
lipoprotein-associated apoC were observed, although there was a decrease in
VLDL-associated apoC-II and C-III-0. Consistent with this finding, the
amount of 125I-labeled apoC transferred from HDL to VLDL in plasma from MDL
29311-treated rats was only 40% of the amount transferred in control
plasma. Sepharose 6B gel filtration of mixtures of 125I-labeled apoC with
increasing concentrations of MDL 29311 in the absence of plasma or lipid
revealed that proportionally increasing amounts of the 125I-labeled apoC
eluted in a high molecular weight (HMW) complex with MDL 29311. An HMW
complex was not formed when MDL 29311 was mixed with 125I-labeled soybean
trypsin inhibitor. The 125I-labeled apoC in the HMW complex bound to VLDL
only 20% as well as uncomplexed 125I-labeled apoC. MDL 29311 also caused
the dissociation of 125I-labeled apoC from VLDL at concentrations of MDL
29311 similar to those obtained in vivo. Other phenolic antioxidants
related to MDL 29311 caused the formation of HMW 125I-labeled
apoC-containing complexes to an extent proportional to their abilities to
lower triglycerides in rats. These studies support the hypothesis that MDL
29311 lowers triglycerides in rats by interfering with apoC association
with VLDL, thereby relieving the apoC- mediated inhibition of hepatic VLDL
uptake.