Inhibition of cholesterol esterification by DuP 128 decreases hepatic apolipoprotein B secretion in vivo: effect of dietary fat and cholesterol.
To further test the hypothesis that newly synthesized cholesteryl esters regulate hepatic apolipoprotein B (apoB) secretion into plasma, apoB kinetic studies were carried out in seven control miniature pigs and in seven animals after 21 days intravenous administration of the acyl coenzyme A:cholesterol acyltransferase (ACAT) inhibitor DuP 128 (2.2 mg/kg/day). Pigs were fed a fat (34% of calories; polyunsaturated/monounsaturated/saturated ratio, 1:1:1) and cholesterol (400 mg/day; 0.1%; 0.2 mg/kcal) containing pig chow based diet. DuP 128 significantly reduced total plasma triglyceride and very low density lipoprotein (VLDL) triglyceride concentrations by 36 and 31%, respectively (P<0.05). Autologous 131I-VLDL and 125I-LDL were injected simultaneously into each pig and apoB kinetic data was analyzed using multicompartmental analysis (SAAM II). The VLDL apoB pool size decreased by 26% (0.443 vs. 0.599 mg/kg; P<0. 001) which was due entirely to a 28% reduction in VLDL apoB production or secretion rate (1.831 vs. 2.548 mg/kg/h; P=0.006). The fractional catabolic rate (FCR) for VLDL apoB was unchanged. The LDL apoB pool size and production rate were unaffected by DuP 128 treatment. Hepatic microsomal ACAT activity decreased by 51% (0.44 vs. 0.90 nmol/min/mg; P<0.001). Although an increase in hepatic free cholesterol and subsequent decrease in both LDL receptor expression and LDL apoB FCR might be expected, this did not occur. The concentration of hepatic free cholesterol decreased 12% (P=0.008) and the LDL apoB FCR were unaffected by DuP 128 treatment. In addition, DuP 128 treatment did not alter the concentration of hepatic triglyceride or the activity of diacylglycerol acyltransferase, indicating a lack of effect of DuP 128 on hepatic triglyceride metabolism. In our previous studies, DuP 128 treatment of miniature pigs fed a low fat, cholesterol free diet, decreased VLDL apoB secretion by 65% resulting in a reduction in plasma apoB of 60%. We conclude that in miniature pigs fed a high fat, cholesterol containing diet, the inhibition of hepatic cholesteryl ester synthesis by DuP 128 decreases apoB secretion into plasma, but the effect is attenuated relative to a low fat, cholesterol free diet.
The Departments of Medicine and Biochemistry and The John P. Robarts Research Institute, 4-16, University of Western Ontario, 100 Perth Drive, London, Ont. N6A 5K8, Canada.
J R
JR
Burnett
L J
LJ
Wilcox
D E
DE
Telford
S J
SJ
Kleinstiver
P H
PH
Barrett
M W
MW
Huff
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001055:Apolipoproteins B / Q000097:blood*; D002791:Cholesterol, Dietary / Q000494:pharmacology*; D004041:Dietary Fats / Q000494:pharmacology*; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology*; D007422:Intestines / Q000201:enzymology; D008079:Lipoproteins, VLDL / Q000097:blood*; D008099:Liver / Q000201:enzymology; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*; D013552:Swine; D013556:Swine, Miniature; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology
D000924:Anticholesteremic Agents; D001055:Apolipoproteins B; D002791:Cholesterol, Dietary; D004041:Dietary Fats; D004791:Enzyme Inhibitors; D007093:Imidazoles; D008079:Lipoproteins, VLDL; D014508:Urea; C084073:lecimibide; D002785:Sterol O-Acyltransferase