title: SC-435, an ileal apical sodium-codependent bile acid transporter inhibitor alters mRNA levels and enzyme activities of selected genes involved in hepatic cholesterol and lipoprotein metabolism in guinea pigs.
abstract: We have demonstrated that SC-435, an apical sodium codependent bile acid transporter (ASBT) inhibitor, lowers plasma low-density lipoprotein cholesterol (LDL-C) concentrations in guinea pigs. The purpose of this study was to further examine the hypocholesterolemic effects of SC-435, by measuring the activity and RNA expression of regulatory enzymes of hepatic cholesterol and lipoprotein metabolism. In addition, the use of a combination (COMBO) therapy with simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, was also tested. Male Hartley guinea pigs were randomly allocated to one of three diets (n=10 per group), for 12 weeks. The control diet contained no ASBT inhibitor or simvastatin. The monotherapy diet (ASBTi) contained 0.1% of SC-435. The COMBO therapy consisted of a lower dose of SC-435 (0.03%) and 0.05% simvastatin. Cholesterol ester transfer protein (CETP) and HMG-CoA reductase mRNA abundance were determined using RT-PCR techniques. Hepatic HMG-CoA reductase and cholesterol 7alpha-hydroxylase (CYP7) activities were measured by radioisotopic methods. Compared to the control group, CETP activity was 34% and 56% lower with ASBTi and COMBO, respectively. Similarly, CETP mRNA expression was reduced by 36% and 73% in ASBTi and COMBO groups, respectively. Cholesterol 7alpha-hydroxylase and HMG-CoA reductase activities were increased approximately 2-fold with ASBTi and COMBO treatments, respectively. Likewise, HMG-CoA reductase mRNA expression was increased 33% with ASBTi treatment. These results suggest that both SC-435 monotherapy and combination therapy lower LDL cholesterol concentrations by altering both hepatic cholesterol homeostasis and the intravascular processing of lipoproteins in guinea pigs.
authors.affiliation: Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA.
authors.forename: Kristy Lynn
authors.initials: KL
authors.lastname: West
authors.forename: Mary
authors.initials: M
authors.lastname: McGrane
authors.forename: Daniel
authors.initials: D
authors.lastname: Odom
authors.forename: Bradley
authors.initials: B
authors.lastname: Keller
authors.forename: Maria Luz
authors.initials: ML
authors.lastname: Fernandez
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics; D002784:Cholesterol / Q000378:metabolism*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism; D053480:Cholesterol Ester Transfer Proteins; D008078:Cholesterol, LDL / Q000097:blood; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D004032:Diet; D004798:Enzymes / Q000235:genetics* / Q000378:metabolism; D006023:Glycoproteins / Q000235:genetics; D006168:Guinea Pigs; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage; D008074:Lipoproteins / Q000378:metabolism*; D008099:Liver / Q000201:enzymology*; D008297:Male; D029363:Organic Anion Transporters, Sodium-Dependent / Q000037:antagonists & inhibitors*; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019821:Simvastatin / Q000008:administration & dosage; D027981:Symporters / Q000037:antagonists & inhibitors*; 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; D001647:Bile Acids and Salts; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D008078:Cholesterol, LDL; D003497:Cyclic N-Oxides; D004798:Enzymes; D006023:Glycoproteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008074:Lipoproteins; D029363:Organic Anion Transporters, Sodium-Dependent; D012333:RNA, Messenger; D027981:Symporters; D014326:Tropanes; C071908:sodium-bile acid cotransporter; D002784:Cholesterol; D019821:Simvastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D002790:Cholesterol 7-alpha-Hydroxylase