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

An orally bioavailable acyl coenzyme A:cholesterol acyltransferase (ACAT) i nhibitor, avasimibe (CI-1011), was used to test the hypothesis that inhibit ion of cholesterol esterification, in vivo, would reduce hepatic very low d ensity (VLDL) apolipoprotein (apo) B secretion into plasma. ApoB kinetic st udies were carried out in 10 control miniature pigs, and in 10 animals trea ted 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%). Ava simibe decreased the plasma concentrations of total triglyceride, VLDL trig lyceride, and VLDL cholesterol by 31-40% 39-48%, and 31-35%, respectively. Significant reductions in plasma total cholesterol (35%) and low density li poprotein (LDL) cholesterol (51%) concentrations were observed only with hi gh dose avasimibe, Autologous I-131-labeled VLDL, I-125-labeled LDL, and [H -3]leucine were injected simultaneously into each pig and apoB kinetic data were analyzed using multicompartmental analysis (SAAM II). Avasimibe decre ased the VLDL apoB pool size by 40-43% and the hepatic secretion rate of VL DL apoB by 38-41%, but did not alter its fractional catabolism, Avasimibe d ecreased 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 abundance s were unchanged, consistent with a marginal decrease in LDL apoB FCRs, Hep atic 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 secre tion correlated with the decrease in hepatic ACAT activity (r = 0.495; P = 0.026). We conclude that inhibition of hepatic ACAT by avasimibe reduces bo th plasma VLDL and LDL apoB concentrations, primarily by decreasing apoB se cretion.