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

John R Burnett,Lisa J Wilcox,Dawn E Telford,Sandra J Kleinstiver,P Hugh R Barrett,Roger S Newton,Murray W Huff

doi:10.1016/s0022-2275(20)33494-5

John R Burnett, Lisa J Wilcox + Show 5 more

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https://doi.org/10.1016/s0022-2275(20)33494-5

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Abstract

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., L. J. Wilcox, D. E. Telford, S. J. Kleinstiver, P. H. R. Barrett, R. S. Newton, and M. W. Huff. Inhibition of ACAT by avasimibe decreases both VLDL and LDL apolipoprotein B production in miniature pigs. J. Lipid Res. 1999. 40: 1317–1327.

Highlights

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 B secretion into plasma
In further studies (25), we have demonstrated that in pigs fed a diet higher in fat, IV DuP 128 treatment resulted in a more modest reduction in very low density lipoprotein (VLDL) apoB secretion
ApoB, apolipoprotein B; VLDL, very low density lipoprotein; LDL, low density lipoprotein; HDL, high density lipoprotein; C, control pigs; A, avasimibe-treated pigs; NS, not significant. a VLDL cholesterol was determined after ultracentrifugation at d Ͻ 1.006 g/mL. b LDL cholesterol was calculated as total cholesterol minus the sum of VLDL cholesterol and HDL cholesterol. c HDL cholesterol was determined after precipitation of the apoB-containing lipoproteins from plasma. d VLDL (d Ͻ 1.006 g/mL) and LDL (d 1.019–1.063 g/mL) apoB are the mean of all samples obtained during the kinetic study in the respective lipoprotein fractions separated by ultracentrifugation

Summary

Present address

ACAT inhibition by DuP 128 did not affect LDL apoB kinetic parameters Consistent with these findings, Carr, Hamilton, and Rudel (19) using perfused monkey livers demonstrated that three different ACAT inhibitors, when added to the liver perfusate, decreased hepatic cholesteryl ester concentrations and apoB secretion (19). Avasimibe (previously known as CI-1011) is a potent, new, orally bioavailable inhibitor of ACAT (26) This compound was effective in decreasing plasma total cholesterol concentrations in cholesterol-fed rats, cholesterol-fed hamsters, casein-fed rabbits, normal chow-fed rats, and chowfed monkeys (26, 27). Koren et al (30) recently demonstrated in hypertriglyceridemic human subjects, that avasimibe treatment (50–500 mg/d) significantly decreased plasma triglyceride and VLDL cholesterol concentrations. An orally bioavailable ACAT inhibitor, avasimibe, was used to test the hypothesis that inhibition of cholesterol esterification, in vivo, would reduce hepatic VLDL apoB secretion into plasma

MATERIALS AND METHODS

RESULTS

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