Inhibition of both the apical sodium-dependent bile acid transporter and HMG-CoA reductase markedly enhances the clearance of LDL apoB.
J Lipid Res
; 44(5): 943-52, 2003 May.
Article
en En
| MEDLINE
| ID: mdl-12562847
ABSTRACT
Discovery of the ileal apical sodium-dependent bile acid transporter (ASBT) permitted development of specific inhibitors of bile acid reabsorption, potentially a new class of cholesterol-lowering agents. In the present study, we tested the hypothesis that combining the novel ASBT inhibitor, SC-435, with the HMG-CoA reductase inhibitor, atorvastatin, would potentiate reductions in LDL cholesterol (LDL-C) and LDL apolipoprotein B (apoB). ApoB kinetic studies were performed in miniature pigs fed a typical human diet and treated with the combination of SC-435 (5 mg/kg/day) plus atorvastatin (3 mg/kg/day) (SC-435+A) or a placebo. SC-435+A decreased plasma total cholesterol by 23% and LDL-C by 40%. Multicompartmental analysis (SAAM II) demonstrated that LDL apoB significantly decreased by 35% due primarily to a 45% increase in the LDL apoB fractional catabolic rate (FCR). SC-435+A significantly decreased hepatic concentrations of free cholesterol and cholesteryl ester, and increased hepatic LDL receptor mRNA consequent to increased cholesterol 7alpha-hydroxylase expression and activity. In comparison, SC-435 (10 mg/kg/day) monotherapy decreased LDL apoB by 10% due entirely to an 18% increase in LDL apoB FCR, whereas atorvastatin monotherapy (3 mg/kg/day) decreased LDL apoB by 30% due primarily to a 22% reduction in LDL apoB production. We conclude that SC-435+A potentiates the reduction of LDL-C and LDL apoB due to complementary mechanisms of action.
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Bases de datos:
MEDLINE
Asunto principal:
Apolipoproteínas B
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Pirroles
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Tropanos
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Proteínas Portadoras
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Inhibidores de Hidroximetilglutaril-CoA Reductasas
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Óxidos N-Cíclicos
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Transportadores de Anión Orgánico Sodio-Dependiente
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Simportadores
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Ácidos Heptanoicos
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Hidroximetilglutaril-CoA Reductasas
Límite:
Animals
Idioma:
En
Revista:
J Lipid Res
Año:
2003
Tipo del documento:
Article
País de afiliación:
Canadá