Inhibition of the apical sodium-dependent bile acid transporter reduces LDL cholesterol and apoB by enhanced plasma clearance of LDL apoB.
OBJECTIVE
Cloning of the ileal apical sodium-dependent bile acid transporter (ASBT) has identified a new pharmacological target for the modulation of plasma lipoproteins. The objective of this study was to determine whether a novel, specific, minimally absorbed ASBT inhibitor (SC-435) decreases LDL cholesterol through the alteration of plasma apoB kinetics.


RESULTS
Miniature pigs were treated for 21 days with 10 mg/kg/day of SC-435 or placebo. SC-435 decreased plasma cholesterol by 9% and LDL cholesterol by 20% with no effect on other lipids. Autologous (131)I-VLDL, (125)I-LDL, and [(3)H]-leucine were injected simultaneously to determine apoB kinetics. LDL apoB concentrations decreased significantly by 10% resulting entirely from an increase in LDL-apoB fractional catabolic rate. SC-435 had no effect on either total LDL apoB production or VLDL apoB converted to LDL. SC-435 increased VLDL apoB production by 22%; however, the concentration was unchanged as a result of increased VLDL apoB direct removal. SC-435 increased hepatic mRNA and enzymatic activity for both cholesterol 7alpha-hydroxylase and HMG-CoA reductase. Hepatic LDL receptor mRNA increased significantly, whereas apoB expression was unaffected.


CONCLUSIONS
A low dose of the ASBT inhibitor, SC-435, significantly reduces plasma LDL cholesterol through enhanced LDL receptor-mediated LDL apoB clearance, secondary to increased expression of cholesterol 7alpha-hydroxylase.
Huff
Murray W
MW
Department of Medicine and Biochemistry and The John P. Robarts Research Institute, The University of Western Ontario, London, Ontario, Canada. mhuff@uwo.ca
Telford
Dawn E
DE
Edwards
Jane Y
JY
Burnett
John R
JR
Barrett
P Hugh R
PH
Rapp
Stephen R
SR
Napawan
Nida
N
Keller
Bradley T
BT
D000818:Animals; D001055:Apolipoproteins B / Q000097:blood* / Q000378:metabolism*; D001647:Bile Acids and Salts / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008078:Cholesterol, LDL / Q000097:blood* / Q000378:metabolism*; D003497:Cyclic N-Oxides / Q000494:pharmacology; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D007700:Kinetics; D050356:Lipid Metabolism; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000097:blood; D008079:Lipoproteins, VLDL / Q000097:blood; D008099:Liver / Q000737:chemistry / Q000201:enzymology; D029363:Organic Anion Transporters, Sodium-Dependent; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000096:biosynthesis; D011973:Receptors, LDL / Q000096:biosynthesis; D013552:Swine; D013556:Swine, Miniature; D027981:Symporters; D014326:Tropanes / Q000494:pharmacology
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; D001647:Bile Acids and Salts; D002352:Carrier Proteins; D008078:Cholesterol, LDL; D003497:Cyclic N-Oxides; D008055:Lipids; D008074:Lipoproteins; D008079:Lipoproteins, VLDL; D029363:Organic Anion Transporters, Sodium-Dependent; D012333:RNA, Messenger; D011973:Receptors, LDL; D027981:Symporters; D014326:Tropanes; C071908:sodium-bile acid cotransporter; D006903:Hydroxymethylglutaryl CoA Reductases