EFFECTS OF STIGMASTANYL-PHOSPHOCHOLINE (RO-16-6532) AND LOVASTATIN ONLIPID AND LIPOPROTEIN LEVELS AND LIPOPROTEIN METABOLISM IN THE HAMSTER ON DIFFERENT DIETS

Previous studies from our laboratory have shown that oral administrati on of stigmastanyl-phosphocholine (Ro 16-6532) reduces plasma choleste rol levels in experimental animals on diets free of added cholesterol. In the present study, effects of Ro 16-6532 and lovastatin on lipopro tein levels and metabolism were investigated in male golden Syrian ham sters. In hamsters fed a standard diet, Po 16-6532 (1 mmol/kg/day) low ered cholesterol in all lipoprotein fractions, as well as apoB-100 and apoA-I. In contrast, lovastatin (25 mu mol/kg/day) lowered high densi ty lipoprotein (HDL)cholesterol but had no effect on low density lipop rotein (LDL)cholesterol or on apoB-100 or apoA-I while triglycerides a nd very low density lipoprotein (VLDL)-cholesterol increased. In hamst ers fed a coconut fat-supplemented diet, Ro 16-6532 reduced all lipopr oteins, with a stronger effect on VLDL and LDL- than on HDL-cholestero l. Also apoB-100 was reduced. Lovastatin (50 mu mol/kg/day) reduced LD L-cholesterol, HDL-cholesterol, and apoA-I while triglycerides and VLD L-cholesterol increased. The drop in LDL-cholesterol seen with both dr ugs in hamsters fed the diet supplemented with coconut fat occurred wi thout any effect on the plasma removal rate of homologous LDL, or on t he content of hepatic LDL-receptors. In contrast, the first phase of r emoval of homologous radioiodinated VLDL from plasma was markedly incr eased by both compounds, paralleled with an increased uptake of label in the liver and a decreased appearance of labeled apoB-100 in the LDL -fraction. Furthermore, retinyl ester-labeled chylomicrons were also c leared more rapidly in hamsters treated with Ro 16-6532. Hepatic uptak e of label from VLDL and chylomicrons was strongly decreased by pre-in jection of lactoferrin. In addition, Po 16-6532 slightly decreased the secretion rate of VLDL in hamsters fed the coconut fat-supplemented d iet. Taken together, these results indicate that the reduction of LDL- cholesterol after treatment with Ro 16-6532 and lovastatin observed in the hamster is mainly due to decreased conversion of VLDL into LDL, c onsequent to an increased hepatic removal of VLDL remnants. Ro 16-6532 also increased the liver uptake of chylomicron remnants. The hepatic uptake system implicated in this remnant removal can be completely blo cked by lactoferrin. The nature of this uptake system is still unknown .