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 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.
Sheetz
M J
MJ
Marion Merrell Dow Research Institute, Cincinnati, OH 45215, USA.
D000818:Animals; D001056:Apolipoproteins C / Q000097:blood*; D001057:Apolipoproteins E / Q000097:blood; D002784:Cholesterol / Q000097:blood; D002850:Chromatography, Gel; D000960:Hypolipidemic Agents / Q000378:metabolism / Q000494:pharmacology*; D008079:Lipoproteins, VLDL / Q000097:blood*; D008297:Male; D011341:Probucol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014280:Triglycerides / Q000097:blood*
D001056:Apolipoproteins C; D001057:Apolipoproteins E; D000960:Hypolipidemic Agents; D008079:Lipoproteins, VLDL; D014280:Triglycerides; C071022:MDL 29311; D002784:Cholesterol; D011341:Probucol