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A more recent version of this article appeared on May 1, 2003

Papers In Press, published online ahead of print February 1, 2003
J. Lipid Res., doi:10.1194/jlr.M200482-JLR200
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Submitted on December 23, 2002
Revised on January 30, 2003
Accepted on January 31, 2003

Inhibition of both the apical sodium-dependent bile acid transporter and HMG-CoA reductase markedly enhances the clearance of LDL apoB

Dawn E. Telford, Jane Y. Edwards, Sara M. Lipson, Brian Sutherland, P. Hugh R. Barrett, John R. Burnett, Elaine S. Krul, Bradley T. Keller, and Murray W. Huff

Vascular Biology Group, The John P. Robarts Research Institute, London, Ontario N6A 5K8

Corresponding Author: mhuff{at}uwo.ca

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 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 (5mg/kg/d) plus atorvastatin (3mg/kg/d) (SC-435+A) or placebo. SC-435+A decreased plasma total-cholesterol by 23% and LDL-cholesterol 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 (10mg/kg/d) monotherapy decreased LDL-apoB by 10%, due entirely to an 18% increase in LDL-apoB FCR, whereas atorvastatin monotherapy (3mg/kg/d) 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-cholesterol and LDL-apoB due to complementary mechanisms of action.


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