title: Inhibition of both the apical sodium-dependent bile acid transporter and HMG-CoA reductase markedly enhances the clearance of LDL apoB.
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.
authors.affiliation: Robarts Research Institute and Departments of Medicine and Biochemistry, University of Western Ontario, London, Ontario, Canada.
authors.forename: Dawn E
authors.initials: DE
authors.lastname: Telford
authors.forename: Jane Y
authors.initials: JY
authors.lastname: Edwards
authors.forename: Sara M
authors.initials: SM
authors.lastname: Lipson
authors.forename: Brian
authors.initials: B
authors.lastname: Sutherland
authors.forename: P Hugh R
authors.initials: PH
authors.lastname: Barrett
authors.forename: John R
authors.initials: JR
authors.lastname: Burnett
authors.forename: Elaine S
authors.initials: ES
authors.lastname: Krul
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Keller
authors.forename: Murray W
authors.initials: MW
authors.lastname: Huff
mesh_terms: D000818:Animals; D001055:Apolipoproteins B / Q000187:drug effects* / Q000378:metabolism; D000069059:Atorvastatin; D002352:Carrier Proteins / Q000187:drug effects* / Q000378:metabolism; D008078:Cholesterol, LDL / Q000097:blood / Q000187:drug effects; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006538:Heptanoic Acids / Q000494:pharmacology*; D006903:Hydroxymethylglutaryl CoA Reductases / Q000187:drug effects* / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007700:Kinetics; D008074:Lipoproteins / Q000097:blood / Q000187:drug effects; D008077:Lipoproteins, LDL / Q000187:drug effects / Q000378:metabolism; D008297:Male; D029363:Organic Anion Transporters, Sodium-Dependent; D011758:Pyrroles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics; D013556:Swine, Miniature; D027981:Symporters; D013997:Time Factors; D014326:Tropanes / Q000494:pharmacology*
chemical_list: C466800:1-(4-(4-(3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl)phenoxy)butyl)-4-aza-1-azoniabicyclo(2.2.2)octane; D001055:Apolipoproteins B; D002352:Carrier Proteins; D008078:Cholesterol, LDL; D003497:Cyclic N-Oxides; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008074:Lipoproteins; D008077:Lipoproteins, LDL; D029363:Organic Anion Transporters, Sodium-Dependent; D011758:Pyrroles; D012333:RNA, Messenger; D011973:Receptors, LDL; D027981:Symporters; D014326:Tropanes; C071908:sodium-bile acid cotransporter; D000069059:Atorvastatin; D006903:Hydroxymethylglutaryl CoA Reductases