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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:1884.)
© 2002 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Inhibition of the Apical Sodium-Dependent Bile Acid Transporter Reduces LDL Cholesterol and ApoB by Enhanced Plasma Clearance of LDL ApoB

Murray W. Huff; Dawn E. Telford; Jane Y. Edwards; John R. Burnett; P. Hugh R. Barrett; Stephen R. Rapp; Nida Napawan; Bradley T. Keller

From the Departments of Medicine and Biochemistry and The John P. Robarts Research Institute (M.W.H., D.E.T., J.Y.E.), The University of Western Ontario, London, Ontario, Canada; the Department of Core Clinical Pathology and Biochemistry, Division of Laboratory Medicine (J.R.B.), Royal Perth Hospital, and Department of Pathology (J.R.B.), University of Western Australia, Perth, West Australia, Australia; Department of Medicine (P.H.R.B.), University of Western Australia and Western Australian Institute for Medical Research, Perth, Western Australia, Australia; Cardiovascular and Metabolic Diseases Discovery Research (S.R.R., N.N., B.T.K.), Pharmacia Corporation, St. Louis, Miss.

Correspondence to Dr Murray Huff, The John P. Robarts Research Institute, 4-16, University of Western Ontario, 100 Perth Drive, London, Ontario N6A 5K8, Canada. E-mail mhuff{at}uwo.ca

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.

Methods and 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 ¹³¹I-VLDL, ¹²⁵I-LDL, and [³H]-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 7-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 7-hydroxylase.

Key Words: apical sodium-dependent bile acid transporter • bile acid reabsorption • apoB kinetics • cholesterol 7-hydroxylase • LDL receptor

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