Effects of stigmastanyl-phosphocholine (Ro 16-6532) and lovastatin on lipid and lipoprotein levels and lipoprotein metabolism in the hamster on different diets.
Previous studies from our laboratory have shown that oral administration of stigmastanyl-phosphocholine (Ro 16-6532) reduces plasma cholesterol levels in experimental animals on diets free of added cholesterol. In the present study, effects of Ro 16-6532 and lovastatin on lipoprotein levels and metabolism were investigated in male golden Syrian hamsters. In hamsters fed a standard diet, Ro 16-6532 (1 mmol/kg/day) lowered cholesterol in all lipoprotein fractions, as well as apoB-100 and apoA-I. In contrast, lovastatin (25 mumol/kg/day) lowered high density lipoprotein (HDL)-cholesterol but had no effect on low density lipoprotein (LDL)-cholesterol or on apoB-100 or apoA-I while triglycerides and very low density lipoprotein (VLDL)-cholesterol increased. In hamsters fed a coconut fat-supplemented diet, Ro 16-6532 reduced all lipoproteins, with a stronger effect on VLDL- and LDL- than on HDL-cholesterol. Also apoB-100 was reduced. Lovastatin (50 mumol/kg/day) reduced LDL-cholesterol, HDL-cholesterol, and apoA-I while triglycerides and VLDL-cholesterol increased. The drop in LDL-cholesterol seen with both drugs in hamsters fed the diet supplemented with coconut fat occurred without any effect on the plasma removal rate of homologous LDL, or on the content of hepatic LDL-receptors. In contrast, the first phase of removal of homologous radioiodinated VLDL from plasma was markedly increased 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 cleared more rapidly in hamsters treated with Ro 16-6532. Hepatic uptake of label from VLDL and chylomicrons was strongly decreased by pre-injection of lactoferrin. In addition, Ro 16-6532 slightly decreased the secretion rate of VLDL in hamsters fed the coconut fat-supplemented diet. 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, consequent 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 blocked by lactoferrin. The nature of this uptake system is still unknown.
Himber
J
J
F. Hoffmann-La Roche AG, Pharma Preclinical Research, Basel, Switzerland.
Missano
B
B
Rudling
M
M
Hennes
U
U
Kempen
H J
HJ
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D016632:Apolipoprotein A-I / Q000378:metabolism; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000097:blood; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary / Q000008:administration & dosage / Q000494:pharmacology; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D015243:Cholesterol, VLDL / Q000097:blood; D000074263:Coconut Oil; D006224:Cricetinae; D004032:Diet; D004041:Dietary Fats / Q000008:administration & dosage / Q000494:pharmacology; D007781:Lactoferrin / Q000494:pharmacology; D008055:Lipids / Q000097:blood*; D008074:Lipoproteins / Q000097:blood*; D008099:Liver / Q000378:metabolism; D008148:Lovastatin / Q000494:pharmacology*; D008297:Male; D008647:Mesocricetus; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010938:Plant Oils / Q000008:administration & dosage; D011973:Receptors, LDL / Q000378:metabolism; D012855:Sitosterols / Q000494:pharmacology*
D000924:Anticholesteremic Agents; D016632:Apolipoprotein A-I; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D002791:Cholesterol, Dietary; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D015243:Cholesterol, VLDL; D004041:Dietary Fats; D008055:Lipids; D008074:Lipoproteins; D010938:Plant Oils; D011973:Receptors, LDL; D012855:Sitosterols; D010767:Phosphorylcholine; D002784:Cholesterol; C072347:stigmastanyl-phosphorylcholine; D008148:Lovastatin; D007781:Lactoferrin; D000074263:Coconut Oil