MDL 29311, an analog of probucol, decreases triglycerides in rats by increasing hepatic clearance of very-low-density lipoprotein

Abstract

MDL 29311 is an analog of probucol that shares probucol's antioxidant and antiatherogenic properties. When fed to rats as a 1% dietary admixture, MDL 29311 decreased triglyceride levels by 65% without affecting total or high-density lipoprotein (HDL) cholesterol levels. Under the same conditions, probucol decreased triglyceride levels by 23% and total cholesterol levels by 29% (with a corresponding decrease in HDL cholesterol level). MDL 29311 treatment did not affect the rate of triglyceride entry into the plasma. However, MDL 29311-treated rats cleared in vivo-labeled very-low-density lipoprotein (VLDL)-associated [ 3H]-triglyceride ([ 3H]-VLDl) over threefold faster than control rats. This increase in clearance led to increased levels of [ 3H]-lipid in liver and decreased ([ 3H]-lipid in fat, muscle, diaphragm, and kidney of MDL 29311-treated rats 1.5 to 2.0 minutes after injection of [ 3H]-VLDL. MDL 29311 treatment had no effect on lipoprotein lipase (LPL) or hepatic triglyceride lipase (H-TGL) activities, or on plasma apolipoprotein (apo) C-II-dependent LPL activation. Intravenously injected [ 3H]-VLDL was allowed to circulate in MDL 29311-treated or control rats for 1 minute, and the undiluted plasma was then perfused through rat livers in a recirculating system. The [ 3H] in MDL 29311 plasma was cleared threefold faster ( t 1 2 , 1.3 v 3.8 minutes ) than the [ 3H] in control plasma by control livers. Conversely, the [ 3H] in control plasma was cleared slowly ( t 1 2 = 3.5 minutes ) by the livers of MDL 29311-treated rats. The [ 3H] in plasma from MDL 29311-treated rats was shown to be predominantly in the form of VLDL (73%), as was the [ 3H] in control plasma (72%). We conclude that MDL 29311 treatment of rats leads to an enhanced liver-mediated clearance of VLDL.