Inhibition of ACAT by avasimibe decreases both VLDL and LDL apolipoprotein B production in miniature pigs.
An orally bioavailable acyl coenzyme A:cholesterol acyltransferase (ACAT) inhibitor, avasimibe (CI-1011), was used to test the hypothesis that inhibition of cholesterol esterification, in vivo, would reduce hepatic very low density (VLDL) apolipoprotein (apo) B secretion into plasma. ApoB kinetic studies were carried out in 10 control miniature pigs, and in 10 animals treated with avasimibe (10 mg/kg/d, n = 6; 25 mg/kg/d, n = 4). Pigs were fed a diet containing fat (34% of calories) and cholesterol (400 mg/d; 0.1%). Avasimibe decreased the plasma concentrations of total triglyceride, VLDL triglyceride, and VLDL cholesterol by 31;-40% 39-48%, and 31;-35%, respectively. Significant reductions in plasma total cholesterol (35%) and low density lipoprotein (LDL) cholesterol (51%) concentrations were observed only with high dose avasimibe. Autologous 131I-labeled VLDL, 125I-labeled LDL, and [3H]leucine were injected simultaneously into each pig and apoB kinetic data were analyzed using multicompartmental analysis (SAAM II). Avasimibe decreased the VLDL apoB pool size by 40;-43% and the hepatic secretion rate of VLDL apoB by 38;-41%, but did not alter its fractional catabolism. Avasimibe decreased the LDL apoB pool size by 13;-57%, largely due to a dose-dependent 25;-63% in the LDL apoB production rate. Hepatic LDL receptor mRNA abundances were unchanged, consistent with a marginal decrease in LDL apoB FCRs. Hepatic ACAT activity was decreased by 51% (P = 0.050) and 68% (P = 0.087) by low and high dose avasimibe, respectively. The decrease in total apoB secretion correlated with the decrease in hepatic ACAT activity (r = 0.495; P = 0.026). We conclude that inhibition of hepatic ACAT by avasimibe reduces both plasma VLDL and LDL apoB concentrations, primarily by decreasing apoB secretion.
Burnett
J R
JR
Departments of Medicine and Biochemistry and The John P. Robarts Research Institute, University of Western Ontario, London, Ontario N6A 5K8, Canada.
Wilcox
L J
LJ
Telford
D E
DE
Kleinstiver
S J
SJ
Barrett
P H
PH
Newton
R S
RS
Huff
M W
MW
D000081:Acetamides; D000085:Acetates; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001055:Apolipoproteins B / Q000096:biosynthesis*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*; D013449:Sulfonamides; D013451:Sulfonic Acids / Q000494:pharmacology*; D013552:Swine; D013556:Swine, Miniature / Q000378:metabolism*
D000081:Acetamides; D000085:Acetates; D000924:Anticholesteremic Agents; D001055:Apolipoproteins B; D004791:Enzyme Inhibitors; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D013449:Sulfonamides; D013451:Sulfonic Acids; C423185:avasimibe; D002785:Sterol O-Acyltransferase