Inhibition of ACAT by avasimibe decreases both VLDL and LDL apolipoprotein B production in miniature pigs

• Published in: Journal of lipid research Vol. 40; no. 7; pp. 1317 - 1327
• Main Authors: Burnett, J R, Wilcox, L J, Telford, D E, Kleinstiver, S J, Barrett, P H, Newton, R S, Huff, M W
• Format: Journal Article
• Language: English
• Published: United States Elsevier 01.07.1999
• Subjects: ACAT inhibitor; Acetates; Animals; Anticholesteremic Agents - pharmacology; apolipoprotein B metabolism; Apolipoproteins B - biosynthesis; avasimibe; Enzyme Inhibitors - pharmacology; Female; kinetics; Lipoproteins, LDL - metabolism; Lipoproteins, VLDL - metabolism; Liver - drug effects; Liver - metabolism; Male; mRNA; Sterol O-Acyltransferase - antagonists & inhibitors; Sulfonic Acids - pharmacology; Swine; Swine, Miniature - metabolism
• ISSN: 0022-2275
• DOI: 10.1016/s0022-2275(20)33494-5

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.