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; Murray W. Huff

Journal of Lipid Research (May 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,
Murray W. Huff

Affiliations

Dawn E. Telford: Robarts Research Institute and Departments of Medicine and Biochemistry, University of Western Ontario, London, Ontario, Canada; Departments of Medicine, University of Western Australia, Perth, Australia; Pathology, University of Western Australia, Perth, Australia; Department of Core Clinical Pathology and Biochemistry, Division of Laboratory Medicine, Royal Perth Hospital, Perth, Australia; Western Australian Institute for Medical Research, Perth, Australia; Cardiovascular and Metabolic Diseases Discovery Research, Pharmacia Corporation, St. Louis, MO 63167
Jane Y. Edwards: Robarts Research Institute and Departments of Medicine and Biochemistry, University of Western Ontario, London, Ontario, Canada; Departments of Medicine, University of Western Australia, Perth, Australia; Pathology, University of Western Australia, Perth, Australia; Department of Core Clinical Pathology and Biochemistry, Division of Laboratory Medicine, Royal Perth Hospital, Perth, Australia; Western Australian Institute for Medical Research, Perth, Australia; Cardiovascular and Metabolic Diseases Discovery Research, Pharmacia Corporation, St. Louis, MO 63167
Sara M. Lipson: Robarts Research Institute and Departments of Medicine and Biochemistry, University of Western Ontario, London, Ontario, Canada; Departments of Medicine, University of Western Australia, Perth, Australia; Pathology, University of Western Australia, Perth, Australia; Department of Core Clinical Pathology and Biochemistry, Division of Laboratory Medicine, Royal Perth Hospital, Perth, Australia; Western Australian Institute for Medical Research, Perth, Australia; Cardiovascular and Metabolic Diseases Discovery Research, Pharmacia Corporation, St. Louis, MO 63167
Brian Sutherland: Robarts Research Institute and Departments of Medicine and Biochemistry, University of Western Ontario, London, Ontario, Canada; Departments of Medicine, University of Western Australia, Perth, Australia; Pathology, University of Western Australia, Perth, Australia; Department of Core Clinical Pathology and Biochemistry, Division of Laboratory Medicine, Royal Perth Hospital, Perth, Australia; Western Australian Institute for Medical Research, Perth, Australia; Cardiovascular and Metabolic Diseases Discovery Research, Pharmacia Corporation, St. Louis, MO 63167
P.Hugh R. Barrett: Robarts Research Institute and Departments of Medicine and Biochemistry, University of Western Ontario, London, Ontario, Canada; Departments of Medicine, University of Western Australia, Perth, Australia; Pathology, University of Western Australia, Perth, Australia; Department of Core Clinical Pathology and Biochemistry, Division of Laboratory Medicine, Royal Perth Hospital, Perth, Australia; Western Australian Institute for Medical Research, Perth, Australia; Cardiovascular and Metabolic Diseases Discovery Research, Pharmacia Corporation, St. Louis, MO 63167
John R. Burnett: Robarts Research Institute and Departments of Medicine and Biochemistry, University of Western Ontario, London, Ontario, Canada; Departments of Medicine, University of Western Australia, Perth, Australia; Pathology, University of Western Australia, Perth, Australia; Department of Core Clinical Pathology and Biochemistry, Division of Laboratory Medicine, Royal Perth Hospital, Perth, Australia; Western Australian Institute for Medical Research, Perth, Australia; Cardiovascular and Metabolic Diseases Discovery Research, Pharmacia Corporation, St. Louis, MO 63167
Elaine S. Krul: Robarts Research Institute and Departments of Medicine and Biochemistry, University of Western Ontario, London, Ontario, Canada; Departments of Medicine, University of Western Australia, Perth, Australia; Pathology, University of Western Australia, Perth, Australia; Department of Core Clinical Pathology and Biochemistry, Division of Laboratory Medicine, Royal Perth Hospital, Perth, Australia; Western Australian Institute for Medical Research, Perth, Australia; Cardiovascular and Metabolic Diseases Discovery Research, Pharmacia Corporation, St. Louis, MO 63167
Bradley T. Keller: Robarts Research Institute and Departments of Medicine and Biochemistry, University of Western Ontario, London, Ontario, Canada; Departments of Medicine, University of Western Australia, Perth, Australia; Pathology, University of Western Australia, Perth, Australia; Department of Core Clinical Pathology and Biochemistry, Division of Laboratory Medicine, Royal Perth Hospital, Perth, Australia; Western Australian Institute for Medical Research, Perth, Australia; Cardiovascular and Metabolic Diseases Discovery Research, Pharmacia Corporation, St. Louis, MO 63167
Murray W. Huff: Robarts Research Institute and Departments of Medicine and Biochemistry, University of Western Ontario, London, Ontario, Canada; Departments of Medicine, University of Western Australia, Perth, Australia; Pathology, University of Western Australia, Perth, Australia; Department of Core Clinical Pathology and Biochemistry, Division of Laboratory Medicine, Royal Perth Hospital, Perth, Australia; Western Australian Institute for Medical Research, Perth, Australia; Cardiovascular and Metabolic Diseases Discovery Research, Pharmacia Corporation, St. Louis, MO 63167

Journal volume & issue: Vol. 44, no. 5
pp. 943 – 952

Abstract

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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 7α-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.

Published in Journal of Lipid Research

ISSN: 0022-2275 (Print); 1539-7262 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science: Chemistry: Organic chemistry: Biochemistry
Website: https://www.journals.elsevier.com/journal-of-lipid-research

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