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

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. 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. Cloning of the ileal apical sodium-dependent bile acid transporter (ASBT) has identified a new pharmacologic target for modulation of plasma lipoproteins (1Wong M.H. Oelkers P. Craddock A.L. Dawson P.A. Expression cloning and characterization of the hamster ileal sodium-dependent bile acid transporter.J. Biol. Chem. 1994; 269: 1340-1347Google Scholar, 2Shneider B.L. Dawson P.A. Christie D.M. Hardikar W. Wong M.H. Suchy F.J. Cloning and molecular characterization of the ontogeny of a rat ileal sodium-dependent bile acid transporter.J. Clin. Invest. 1995; 95: 745-754Google Scholar, 3Love M.W. Dawson P.A. New insights into bile acid transport.Curr. Opin. Lipidol. 1998; 9: 225-229Google Scholar, 4Meier P.J. Eckhardt U. Schroeder A. Hagenbuch B. Stieger B. Substrate specificity of sinusoidal bile acid and organic anion uptake systems in rat and human liver.Hepatology. 1997; 26: 1667-1677Google Scholar). SC-435 is a potent specific inhibitor of the ASBT, resulting in interruption of the enterohepatic circulation of bile acids and ultimately leading to decreased LDL cholesterol (LDL-C) in a variety of animal models (5Huff M.W. Telford D.E. Edwards J.Y. Burnett J.R. Barrett P.H.R. Rapp S.R. Napawan N. Keller B.T. Inhibition of the apical sodium-dependent bile acid transporter reduces LDL cholesterol and apoB by enhanced plasma clearance of LDL apoB.Arterioscler. Thromb. Vasc. Biol. 2002; 22: 1884-1891Google Scholar, 6Rapp S.R. Bhat B.G. Beaudry J.A. Napawan N. Keller B.T. SC-435 is a potent inhibitor of the apical sodium co-dependent bile acid transporter (ASBT) in mice, rats, hamsters and dogs and reduces atherosclerotic lesions in apoE−/− mice.in: XIV International Symposium on Drugs Affecting Lipid Metabolism. Fondazione Giovanni Lorenzini Foundation, Milan2001: 50Google Scholar, 7West K.L. Ramjiganesh T. Roy S. Keller B.T. Fernandez M.L. 1-[4-[4-[(4R,5R)-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 methanesulfonate (SC-435), an ileal apical sodium-codependent bile acid transporter inhibitor alters hepatic cholesterol metabolism and lowers plasma low-density lipoprotein-cholesterol concentrations in guinea pigs.J. Pharmacol. Exp. Ther. 2002; 303: 293-299Google Scholar). In vitro, SC-435 inhibits uptake of bile acids in BHK cells transfected with the human ASBT gene with an IC50 of 1.5 nM (6Rapp S.R. Bhat B.G. Beaudry J.A. Napawan N. Keller B.T. SC-435 is a potent inhibitor of the apical sodium co-dependent bile acid transporter (ASBT) in mice, rats, hamsters and dogs and reduces atherosclerotic lesions in apoE−/− mice.in: XIV International Symposium on Drugs Affecting Lipid Metabolism. Fondazione Giovanni Lorenzini Foundation, Milan2001: 50Google Scholar). In vivo, we recently demonstrated that, in miniature pigs fed normal amounts of fat and cholesterol, SC-435 enhanced bile acid excretion, leading to a significant 20% reduction in LDL-C (5Huff M.W. Telford D.E. Edwards J.Y. Burnett J.R. Barrett P.H.R. Rapp S.R. Napawan N. Keller B.T. Inhibition of the apical sodium-dependent bile acid transporter reduces LDL cholesterol and apoB by enhanced plasma clearance of LDL apoB.Arterioscler. Thromb. Vasc. Biol. 2002; 22: 1884-1891Google Scholar). Apolipoprotein B (apoB) kinetic studies revealed that SC-435 treatment increased LDL apoB clearance, mediated by enhanced hepatic expression of LDL receptors secondary to upregulation of hepatic cholesterol 7α-hydroxylase (CYP7A1) expression. with the molecular for recently by for of bile acid by Scholar). of bile acids due to a in to the reduces the receptor of the in for the of the receptor is a for the ASBT gene Dawson P.A. F.J. B.L. receptor and of the apical sodium-dependent bile acid transporter.J. Biol. Chem. and the gene S. B. an receptor that expression of the human cholesterol 7α-hydroxylase Scholar, B. S.R. of the receptors and bile acid Scholar). the of is the for the of cholesterol to bile acids in B.L. bile acid and increase in cholesterol 7α-hydroxylase in a in hepatic in the of to cholesterol upregulation of LDL receptor expression (5Huff M.W. Telford D.E. Edwards J.Y. Burnett J.R. Barrett P.H.R. Rapp S.R. Napawan N. Keller B.T. Inhibition of the apical sodium-dependent bile acid transporter reduces LDL cholesterol and apoB by enhanced plasma clearance of LDL apoB.Arterioscler. Thromb. Vasc. Biol. 2002; 22: 1884-1891Google Scholar). We that SC-435 increased the hepatic expression of HMG-CoA reductase and cholesterol the reduction in LDL-C (5Huff M.W. Telford D.E. Edwards J.Y. Burnett J.R. Barrett P.H.R. Rapp S.R. Napawan N. Keller B.T. Inhibition of the apical sodium-dependent bile acid transporter reduces LDL cholesterol and apoB by enhanced plasma clearance of LDL apoB.Arterioscler. Thromb. Vasc. Biol. 2002; 22: 1884-1891Google Scholar). In reduction of cholesterol by inhibitors of HMG-CoA reductase in cholesterol lowers LDL-C and of cholesterol in with the 1994; Scholar, of with in with 1995; Scholar, of on in with cholesterol Scholar, with in of and with in with and a of cholesterol 1998; Scholar, of cholesterol with in a 2002; Scholar). In vivo, apoB kinetic studies demonstrated that LDL clearance of and the of to apoB is a in M.W. Burnett J.R. reductase inhibitors and hepatic apolipoprotein B Opin. Lipidol. 1997; with and bile acid has to for LDL-C reduction in human and treatment A. of and in combination with on apolipoprotein B Thromb. Vasc. Biol. Scholar, M.W. Telford D.E. of B metabolism by and in miniature on LDL and of LDL Scholar, M.W. Telford D.E. and the of apolipoprotein B in miniature pigs.J. Lipid 26: Scholar, of with and in on of apolipoprotein 9: Scholar). that combination of the ASBT inhibitor SC-435 and a would significantly the reduction in plasma LDL-C and apoB complementary mechanisms of action. In the present study, we tested in miniature pigs the hypothesis that the upregulation of hepatic cholesterol with potentiates the of LDL-C by apoB kinetic studies were to the for in We that the combination of SC-435 and atorvastatin significantly enhanced LDL-C reductions in LDL apoB concentrations were significantly decreased primarily due to an increase in the LDL apoB fractional catabolic rate (FCR). increase in apoB rate with SC-435 by combination SC-435 plus atorvastatin significantly increased hepatic expression of cholesterol resulting in decreased hepatic free cholesterol and cholesteryl ester, and increased hepatic expression of the LDL pigs were and were in for were on the diet for to to a or the ASBT inhibitor, SC-435, a of with atorvastatin a of SC-435 is a inhibitor methanesulfonate that by specificity of SC-435 for ASBT has (5Huff M.W. Telford D.E. Edwards J.Y. Burnett J.R. Barrett P.H.R. Rapp S.R. Napawan N. Keller B.T. Inhibition of the apical sodium-dependent bile acid transporter reduces LDL cholesterol and apoB by enhanced plasma clearance of LDL apoB.Arterioscler. Thromb. Vasc. Biol. 2002; 22: 1884-1891Google Scholar). of apoB kinetic studies were the to study, an in an M.W. Telford D.E. and the of apolipoprotein B in miniature pigs.J. Lipid 26: Scholar). the and the by with for of in J.R. Telford D.E. Barrett P.H.R. M.W. Inhibition of HMG-CoA reductase by atorvastatin and LDL apolipoprotein B in miniature Thromb. Vasc. Biol. 1997; Scholar). by the of the of SC-435 plus atorvastatin or a in to by to the animal a of a diet fat of acid of and cholesterol J.R. Telford D.E. Barrett P.H.R. M.W. Inhibition of HMG-CoA reductase by atorvastatin and LDL apolipoprotein B in miniature Thromb. Vasc. Biol. 1997; Scholar). the of SC-435 plus atorvastatin pigs were and of the and were in studies were performed with J.R. Telford D.E. Barrett P.H.R. M.W. Inhibition of HMG-CoA reductase by atorvastatin and LDL apolipoprotein B in miniature Thromb. Vasc. Biol. 1997; Scholar, J.R. Telford D.E. Barrett P.H.R. M.W. of in hepatic apolipoprotein B is by the of reductase in miniature Scholar). In and LDL plasma a were by and with and M.W. Telford D.E. and the of apolipoprotein B in miniature pigs.J. Lipid 26: Scholar). lipoproteins were the total free to and of the to the total LDL free to and of the to a animal and specific a by the of diet and the study, and plasma apoB and plasma were J.R. Telford D.E. Barrett P.H.R. M.W. Inhibition of HMG-CoA reductase by atorvastatin and LDL apolipoprotein B in miniature Thromb. Vasc. Biol. 1997; Scholar). and LDL apoB concentrations were the were the (SAAM on a the in the and the to the were J.R. Telford D.E. Barrett P.H.R. M.W. Inhibition of HMG-CoA reductase by atorvastatin and LDL apolipoprotein B in miniature Thromb. Vasc. Biol. 1997; Scholar, M.W. Telford D.E. Barrett P.H.R. P.J. Inhibition of hepatic apoB in miniature pigs fed a Thromb. Vasc. Biol. 1994; Scholar). the for the of the and apoB of the by the were into the the in of the the and for plasma apoB and and LDL J.R. Telford D.E. Barrett P.H.R. M.W. Inhibition of HMG-CoA reductase by atorvastatin and LDL apolipoprotein B in miniature Thromb. Vasc. Biol. 1997; Scholar). and were the to the and of in is the of rate for a kinetic and rate and the of the J.R. Telford D.E. Barrett P.H.R. M.W. Inhibition of HMG-CoA reductase by atorvastatin and LDL apolipoprotein B in miniature Thromb. Vasc. Biol. 1997; Scholar). to the of for the the the and the LDL the the of the and the for the and the of for were of that and (5Huff M.W. Telford D.E. Edwards J.Y. Burnett J.R. Barrett P.H.R. Rapp S.R. Napawan N. Keller B.T. Inhibition of the apical sodium-dependent bile acid transporter reduces LDL cholesterol and apoB by enhanced plasma clearance of LDL apoB.Arterioscler. Thromb. Vasc. Biol. 2002; 22: 1884-1891Google Scholar, J.R. Telford D.E. Barrett P.H.R. M.W. Inhibition of HMG-CoA reductase by atorvastatin and LDL apolipoprotein B in miniature Thromb. Vasc. Biol. 1997; Scholar). were and were the of for the and of total animal Biol. Chem. Scholar). cholesterol, free cholesterol, and concentrations were in hepatic total and J.R. Telford D.E. Barrett P.H.R. M.W. Inhibition of HMG-CoA reductase by atorvastatin and LDL apolipoprotein B in miniature Thromb. Vasc. Biol. 1997; Scholar). were by for by of the for (5Huff M.W. Telford D.E. Edwards J.Y. Burnett J.R. Barrett P.H.R. Rapp S.R. Napawan N. Keller B.T. Inhibition of the apical sodium-dependent bile acid transporter reduces LDL cholesterol and apoB by enhanced plasma clearance of LDL apoB.Arterioscler. Thromb. Vasc. Biol. 2002; 22: 1884-1891Google Scholar). the and for resulting and for resulting hepatic to cholesterol 7α-hydroxylase and HMG-CoA reductase activity. 7α-hydroxylase in hepatic a (5Huff M.W. Telford D.E. Edwards J.Y. Burnett J.R. Barrett P.H.R. Rapp S.R. Napawan N. Keller B.T. Inhibition of the apical sodium-dependent bile acid transporter reduces LDL cholesterol and apoB by enhanced plasma clearance of LDL apoB.Arterioscler. Thromb. Vasc. Biol. 2002; 22: 1884-1891Google of a of cholesterol Scholar). of of HMG-CoA reductase in hepatic a (5Huff M.W. Telford D.E. Edwards J.Y. Burnett J.R. Barrett P.H.R. Rapp S.R. Napawan N. Keller B.T. Inhibition of the apical sodium-dependent bile acid transporter reduces LDL cholesterol and apoB by enhanced plasma clearance of LDL apoB.Arterioscler. Thromb. Vasc. Biol. 2002; 22: 1884-1891Google of the of and on the of cholesterol 7α-hydroxylase and HMG-CoA reductase in rat of and of the Lipid Scholar). of of of and cholesteryl in or rate of of into cholesteryl and by T. P. A. W. In that the of the inhibitor in is due to of and Lipid Scholar). were to apoB LDL receptor cholesterol 7α-hydroxylase human HMG-CoA reductase and (5 were by for with and were for the gene of with the for were to total or treated and for and and analysis of J.A. in New Scholar). were for with of and with were were a and for the gene of with for were on and of the study, and plasma concentrations of total cholesterol and and and were M.W. Telford D.E. and the of apolipoprotein B in miniature pigs.J. Lipid 26: Scholar). and of lipoproteins by M.W. Telford D.E. and the of apolipoprotein B in miniature pigs.J. Lipid 26: Scholar). LDL-C by concentrations of total cholesterol, free cholesterol, cholesteryl ester, and were in the plasma and M.W. Telford D.E. and the of apolipoprotein B in miniature pigs.J. Lipid 26: Scholar). and combination treatment were for by monotherapy treatment and combination treatment were for by of SC-435 (5 mg/kg/day) and atorvastatin (3 SC-435 that in monotherapy (5Huff M.W. Telford D.E. Edwards J.Y. Burnett J.R. Barrett P.H.R. Rapp S.R. Napawan N. Keller B.T. Inhibition of the apical sodium-dependent bile acid transporter reduces LDL cholesterol and apoB by enhanced plasma clearance of LDL apoB.Arterioscler. Thromb. Vasc. Biol. 2002; 22: 1884-1891Google in bile acid increased and LDL-C by we demonstrated that of atorvastatin in a LDL-C reduction of 30% J.R. Telford D.E. Barrett P.H.R. M.W. Inhibition of HMG-CoA reductase by atorvastatin and LDL apolipoprotein B in miniature Thromb. Vasc. Biol. 1997; Scholar). were for in to to a of SC-435 potentiate the of a of atorvastatin on plasma LDL-C concentrations and plasma apoB of SC-435 with atorvastatin on plasma and concentrations of treatment is in treatment significantly total plasma cholesterol by 23% and LDL-C by plasma and apoB concentrations were whereas LDL apoB decreased by 35% and concentrations in and SC-435 plus miniature is a of cholesterol LDL cholesterol total cholesterol the of cholesterol and cholesterol of the lipoproteins and LDL to apoB the of the in the by in a new is a of cholesterol LDL cholesterol total cholesterol the of cholesterol and cholesterol of the lipoproteins and LDL to apoB the of the in the by and were into and treated with SC-435 plus kinetic of apoB were the analysis of the specific the models J.R. Telford D.E. Barrett P.H.R. M.W. Inhibition of HMG-CoA reductase by atorvastatin and LDL apolipoprotein B in miniature Thromb. Vasc. Biol. 1997; Scholar, J.R. Telford D.E. Barrett P.H.R. M.W. of in hepatic apolipoprotein B is by the of reductase in miniature Scholar, M.W. Telford D.E. Barrett P.H.R. P.J. Inhibition of hepatic apoB in miniature pigs fed a Thromb. Vasc. Biol. 1994; Scholar). kinetic for apoB and LDL apoB in and of the to the for and LDL the of for a of is in of apoB metabolism in and SC-435 plus miniature to the plasma apoB by with the that in the plasma is by apoB is the rate of the in to the of the to to LDL a of total a of total fractional catabolic were by to the plasma apoB by with the that in the plasma is by apoB is the rate of the in to the of the to LDL a of total a of total production. in a new of LDL apoB metabolism in and SC-435 plus miniature to the plasma LDL apoB by with the that in the plasma is the rate the is the of apoB into apoB of apoB into the plasma apoB plus LDL apoB a of total LDL were by to the plasma LDL apoB by with the that in the plasma is the rate the is the of apoB into LDL a of total LDL of apoB into the plasma apoB plus LDL apoB production. in a new FCR, fractional catabolic were by were by treatment or on the apoB kinetic apoB FCR, and were the of apoB to LDL apoB the of apoB to or LDL by combination of apoB to LDL apoB and the were by SC-435 plus In apoB kinetic were by treatment SC-435 plus atorvastatin treatment significantly decreased the LDL apoB by 35% primarily due to a 45% increase in the LDL apoB treatment on the total rate of LDL apoB or on the of LDL apoB apoB LDL apoB LDL apoB the plasma metabolism the plasma or decreased by of of apoB into plasma plus LDL decreased by kinetic for apoB into plasma and the in pigs treated with SC-435 and atorvastatin with in apoB were by combination LDL apoB significantly primarily due to an increase in the LDL apoB FCR, LDL apoB significantly of for a of apoB in pigs treated with SC-435 plus atorvastatin, and pigs treated with SC-435 recently and performed an to that of the present (5Huff M.W. Telford D.E. Edwards J.Y. Burnett J.R. Barrett P.H.R. Rapp S.R. Napawan N. Keller B.T. Inhibition of the apical sodium-dependent bile acid transporter reduces LDL cholesterol and apoB by enhanced plasma clearance of LDL apoB.Arterioscler. Thromb. Vasc. Biol. 2002; 22: 1884-1891Google Scholar). increase in apoB with SC-435 by combination treatment a the apoB increased with SC-435 whereas apoB with combination treatment decreased the LDL apoB to a that with SC-435 and the LDL apoB increased to a with combination treatment with SC-435 and LDL were for and in SC-435 in combination with atorvastatin in a in the of cholesteryl in of and were significantly treatment increased the of in LDL by decreased the of cholesteryl by and increased the of by of of in LDL increased by of to that combination LDL of and LDL and SC-435 plus miniature and and of to cholesteryl is the of of total and of on and LDL and SC-435 plus of to cholesteryl is the of in a new of total and of on and LDL and SC-435 plus the of the pigs were and of and were and to concentrations of free cholesterol and cholesteryl were decreased by and decreased by in hepatic free cholesterol cholesteryl and were the cholesteryl reduction significant concentrations were by combination treatment of cholesterol 7α-hydroxylase increased in hepatic by SC-435 plus atorvastatin with a the of HMG-CoA reductase increased in the of treated of into cholesteryl and in significant were for with combination into cholesteryl and in the were by treatment and mRNA expression in and SC-435 plus miniature and and by in of of to of the for and SC-435 plus atorvastatin were the of SC-435 plus atorvastatin or placebo. of were and of cholesterol 7α-hydroxylase and HMG-CoA reductase were in hepatic into cholesteryl and in and free cholesterol, cholesteryl ester, and concentrations were in and hepatic by in and by in of of to in a new the for and SC-435 plus atorvastatin were the of SC-435 plus atorvastatin or placebo. of were and of cholesterol 7α-hydroxylase and HMG-CoA reductase were in hepatic into cholesteryl and in and free cholesterol, cholesteryl ester, and concentrations were in and hepatic by in concentrations of mRNA for the LDL cholesterol and HMG-CoA reductase were increased by combination treatment mRNA of the LDL receptor increased of cholesterol 7α-hydroxylase increased and of HMG-CoA reductase increased apoB mRNA the and apoB kinetic in for treatment with SC-435 (5 mg/kg/day) plus atorvastatin (3 in studies SC-435 monotherapy (10 mg/kg/day) (5Huff M.W. Telford D.E. Edwards J.Y. Burnett J.R. Barrett P.H.R. Rapp S.R. Napawan N. Keller B.T. Inhibition of the apical sodium-dependent bile acid transporter reduces LDL cholesterol and apoB by enhanced plasma clearance of LDL apoB.Arterioscler. Thromb. Vasc. Biol. 2002; 22: 1884-1891Google atorvastatin monotherapy (3 mg/kg/day) J.R. Telford D.E. Barrett P.H.R. M.W. Inhibition of HMG-CoA reductase by atorvastatin and LDL apolipoprotein B in miniature Thromb. Vasc. Biol. 1997; or atorvastatin monotherapy (10 mg/kg/day) J.R. Telford D.E. Barrett P.H.R. M.W. of in hepatic apolipoprotein B is by the of reductase in miniature in In reductions in LDL-C and LDL apoB concentrations with combination were with of SC-435 or atorvastatin (3 mg/kg/day) in were to with in total LDL apoB with combination were with of atorvastatin, with SC-435 the increase in LDL apoB with combination treatment that with monotherapy with SC-435 or atorvastatin a with to LDL apoB of ASBT and the of the of the of cholesterol 7α-hydroxylase has on the enterohepatic circulation of bile acids an for treatment of (1Wong M.H. Oelkers P. Craddock A.L. Dawson P.A. Expression cloning and characterization of the hamster ileal sodium-dependent bile acid transporter.J. Biol. Chem. 1994; 269: 1340-1347Google Scholar, 2Shneider B.L. Dawson P.A. Christie D.M. Hardikar W. Wong M.H. Suchy F.J. Cloning and molecular characterization of the ontogeny of a rat ileal sodium-dependent bile acid transporter.J. Clin. Invest. 1995; 95: 745-754Google Scholar, 3Love M.W. Dawson P.A. New insights into bile acid transport.Curr. Opin. Lipidol. 1998; 9: 225-229Google Scholar, for of bile acid by Scholar, S. B. an receptor that expression of the human cholesterol 7α-hydroxylase Scholar, B. S.R. of the receptors and bile acid Scholar, P.A. the of and and in Lipid 2002; Scholar). ASBT has an target for due to in bile acid and to the of the has the development of specific ASBT the of to the metabolism of hepatic cholesterol, ultimately resulting in significant reductions in plasma LDL-C (6Rapp S.R. Bhat B.G. Beaudry J.A. Napawan N. Keller B.T. SC-435 is a potent inhibitor of the apical sodium co-dependent bile acid transporter (ASBT) in mice, rats, hamsters and dogs and reduces atherosclerotic lesions in apoE−/− mice.in: XIV International Symposium on Drugs Affecting Lipid Metabolism. Fondazione Giovanni Lorenzini Foundation, Milan2001: 50Google Scholar, W. acid systems Clin. Invest. 26: Scholar, Inhibition of ileal sodium-dependent bile acid by Lipid 1995; Scholar, S. N. T. an ileal acid inhibitor cholesterol in 1997; Scholar). we that treatment of miniature pigs with the ASBT inhibitor SC-435 significantly decreased LDL-C and apoB (5Huff M.W. Telford D.E. Edwards J.Y. Burnett J.R. Barrett P.H.R. Rapp S.R. Napawan N. Keller B.T. Inhibition of the apical sodium-dependent bile acid transporter reduces LDL cholesterol and apoB by enhanced plasma clearance of LDL apoB.Arterioscler. Thromb. Vasc. Biol. 2002; 22: 1884-1891Google Scholar). for enhanced LDL apoB clearance, mediated by increased expression of hepatic LDL secondary to of hepatic cholesterol increase in hepatic HMG-CoA reductase expression and that the of cholesterol in to of bile acid for the plasma In the present study, we that of hepatic cholesterol with the HMG-CoA reductase inhibitor atorvastatin would increase in and in a reduction in plasma cholesterol with the ASBT inhibitor combination of SC-435 and atorvastatin a significantly enhanced reduction in LDL-C of SC-435 LDL apoB decreased by SC-435 reduction in LDL apoB primarily due to a 45% increase in LDL apoB clearance, mediated by enhanced hepatic LDL receptor expression consequent to upregulation of hepatic cholesterol 7α-hydroxylase and expression and decreased cholesterol to we that SC-435 of the ASBT in animal to increased bile acid and upregulation of cholesterol 7α-hydroxylase expression and (5Huff M.W. Telford D.E. Edwards J.Y. Burnett J.R. Barrett P.H.R. Rapp S.R. Napawan N. Keller B.T. Inhibition of the apical sodium-dependent bile acid transporter reduces LDL cholesterol and apoB by enhanced plasma clearance of LDL apoB.Arterioscler. Thromb. Vasc. Biol. 2002; 22: 1884-1891Google Scholar). SC-435 with atorvastatin, cholesterol 7α-hydroxylase to a would to the enterohepatic circulation of bile acids cholesterol 7α-hydroxylase activity. the of HMG-CoA reductase by atorvastatin in an of HMG-CoA reductase the of and a of a for cholesterol Scholar, of HMG-CoA the of Scholar). the to HMG-CoA reductase and expression in the of a is to the of HMG-CoA reductase J.R. Telford D.E. Barrett P.H.R. M.W. of in hepatic apolipoprotein B is by the of reductase in miniature Scholar). that the increase in hepatic cholesterol resulting the increase in cholesterol 7α-hydroxylase by the of hypothesis that combination the reduction of a of hepatic cholesterol for the of LDL receptor expression. In significant reductions in free cholesterol and cholesteryl concentrations were and in hepatic cholesteryl concentrations were and a a free cholesterol with of the of hepatic cholesterol the molecular for of bile acid by Scholar, S. B. an receptor that expression of the human cholesterol 7α-hydroxylase Scholar, B. S.R. of the receptors and bile acid Scholar). of bile acid to the would the of the of would the of to and is an of the cholesterol 7α-hydroxylase gene would increase the of hepatic cholesterol to bile reduction in the hepatic of cholesterol would enhanced by the HMG-CoA reductase inhibitor atorvastatin, leading to a increase in LDL receptor expression. in study, is that mediated by an increase in the of is a of LDL receptor and HMG-CoA reductase expression Expression of mRNA in rat cells of were to increase in is that increased LDL receptor expression mediated by of the of is of hepatic acid and Expression of mRNA in rat cells of were by combination is with the of of and in hamster 1995; that, in treatment with the bile acid and the HMG-CoA reductase inhibitor increased the hepatic of whereas that of We that the reduction in hepatic cholesterol to the increased of cholesterol 7α-hydroxylase and of cholesterol would the of for M.W. Burnett J.R. reductase inhibitors and hepatic apolipoprotein B Opin. Lipidol. 1997; Scholar). studies in pigs treated with atorvastatin demonstrated significant in to reductions in hepatic cholesterol and cholesteryl concentrations J.R. Telford D.E. Barrett P.H.R. M.W. Inhibition of HMG-CoA reductase by atorvastatin and LDL apolipoprotein B in miniature Thromb. Vasc. Biol. 1997; Scholar, J.R. Telford D.E. Barrett P.H.R. M.W. of in hepatic apolipoprotein B is by the of reductase in miniature Scholar). combination treatment on apoB with studies SC-435 monotherapy in pigs increased (5Huff M.W. Telford D.E. Edwards J.Y. Burnett J.R. Barrett P.H.R. Rapp S.R. Napawan N. Keller B.T. Inhibition of the apical sodium-dependent bile acid transporter reduces LDL cholesterol and apoB by enhanced plasma clearance of LDL apoB.Arterioscler. Thromb. Vasc. Biol. 2002; 22: 1884-1891Google Scholar). We that, increased in treated with bile acid B. B. of and acid on the metabolism of in Lipid the we in pigs to in hepatic were (5Huff M.W. Telford D.E. Edwards J.Y. Burnett J.R. Barrett P.H.R. Rapp S.R. Napawan N. Keller B.T. Inhibition of the apical sodium-dependent bile acid transporter reduces LDL cholesterol and apoB by enhanced plasma clearance of LDL apoB.Arterioscler. Thromb. Vasc. Biol. 2002; 22: 1884-1891Google Scholar). of in with combination that the for the enhanced apoB by SC-435 by the of LDL a to the in LDL apoB is with in LDL in pigs treated with plus M.W. Telford D.E. of B metabolism by and in miniature on LDL and of LDL Scholar, M.W. Telford D.E. and the of apolipoprotein B in miniature pigs.J. Lipid 26: Scholar). we in in pigs treated with atorvastatin monotherapy J.R. Telford D.E. Barrett P.H.R. M.W. Inhibition of HMG-CoA reductase by atorvastatin and LDL apolipoprotein B in miniature Thromb. Vasc. Biol. 1997; Scholar, J.R. Telford D.E. Barrett P.H.R. M.W. of in hepatic apolipoprotein B is by the of reductase in miniature Scholar). In the LDL apoB significantly a of decreased LDL consequent to decreased with an increased LDL apoB SC-435 plus atorvastatin significantly the of a in cholesteryl and a to is that to the increase in LDL apoB in LDL with decreased cholesteryl resulting in LDL with an increase in LDL apoB in guinea pigs treated with in and in the guinea Lipid 26: or of on guinea and Lipid Scholar). We conclude that SC-435 plus atorvastatin potentiates the reduction of LDL-C and apoB complementary mechanisms of action. In a animal of human bile acid with a specific inhibitor of the ASBT and the increase in cholesterol with atorvastatin in reductions in LDL-C and LDL is increased LDL clearance, is mediated enhanced hepatic expression of LDL receptors to a combination of increased hepatic cholesterol 7α-hydroxylase and decreased cholesterol of the ileal ASBT a new treatment for in combination with an for target by a the and of to the of and is a of the of is a of the and of for the and and Napawan for apical sodium-dependent bile acid transporter fractional catabolic rate receptor receptor

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