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.
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.
West
Kristy Lynn
KL
Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA.
McGrane
Mary
M
Odom
Daniel
D
Keller
Bradley
B
Fernandez
Maria Luz
ML
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*
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