Inhibition of hepatic ACAT decreases ApoB secretion in miniature pigs fed a cholesterol-free diet.
To test the hypothesis that hepatic cholesteryl ester is involved in the regulation of apolipoprotein (apo) B secretion into plasma, apoB kinetic studies were performed in six control miniature pigs and in six pigs after a 21-day administration of the acyl coenzyme A:cholesterol acyltransferase (ACAT) inhibitor DuP 128 (2.2 mg.kg-1.d-1 i.v.). Pigs were fed low-fat, cholesterol-free diets. Total plasma cholesterol, triglyceride, very-low-density lipoprotein (VLDL) triglyceride, and low-density lipoprotein (LDL) cholesterol decreased 18%, 29%, 40%, and 26% respectively (P < .03). 131I-VLDL and 125I-LDL were injected simultaneously into each animal, and apoB kinetics were analyzed by using multi-compartmental analysis (SAAM30). VLDL apoB pool size decreased significantly by 60% (0.32 versus 0.84 mg/kg), which was due to a 65% reduction in the VLDL apoB production or secretion rate (1.03 versus 2.94 mg.kg-1.h-1). The fractional catabolic rate was unchanged. LDL apoB pool size decreased nonsignificantly by 18% (5.61 versus 6.90 mg/kg) due entirely to a 24% decrease in production rate (0.26 versus 0.34 mg.kg-1.h-1). At necropsy, hepatic microsomal ACAT activity decreased by 68% (0.28 versus 0.88 nmol.min-1.mg-1; P < .0002). Although an increase in hepatic free cholesterol leading to a decreased LDL receptor expression might be expected, this did not occur. The concentration of hepatic cholesterol and the LDL apoB fractional catabolic rate were unaffected by DuP 128. In addition, the concentration of hepatic triglyceride and the activity of diacylglycerol acyltransferase were not altered by DuP 128, indicating a lack of effect of DuP 128 on hepatic triglyceride metabolism. We conclude that inhibition of hepatic cholesteryl ester synthesis in vivo decreases apoB secretion into plasma.
Huff
M W
MW
Department of Medicine, University of Western Ontario, London, Canada.
Telford
D E
DE
Barrett
P H
PH
Billheimer
J T
JT
Gillies
P J
PJ
D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism*; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary / Q000008:administration & dosage*; D008078:Cholesterol, LDL / Q000097:blood; D007093:Imidazoles / Q000494:pharmacology; D007700:Kinetics; D008079:Lipoproteins, VLDL / Q000097:blood; D008099:Liver / Q000201:enzymology*; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*; D013552:Swine; D013556:Swine, Miniature; D014280:Triglycerides / Q000097:blood; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
D001055:Apolipoproteins B; D002791:Cholesterol, Dietary; D008078:Cholesterol, LDL; D007093:Imidazoles; D008079:Lipoproteins, VLDL; D014280:Triglycerides; D014508:Urea; D002784:Cholesterol; C084073:lecimibide; D002785:Sterol O-Acyltransferase