Title

SC-435, an ileal apical sodium co-dependent bile acid transporter (ASBT) inhibitor: Hypocholesterolemic mechanisms of action in the guinea pig

Date of Completion

January 2004

Keywords

Chemistry, Biochemistry|Health Sciences, Nutrition

Degree

Ph.D.

Abstract

The causal relation between elevated cholesterol levels and the development of Coronary Heart Disease (CHD) and atherosclerosis has been well documented. Ileal bile acid transport is mediated by the apical sodium co-dependent bile acid transporter (ASBT). Partial inhibition of ASBT function may have important therapeutic applications. SC-435 was recently identified as a specific, non-absorbable ASBT inhibitor (ASBTi). The present studies were conducted to evaluate the mechanisms by which the ASBT inhibitor, SC-435, reduces plasma cholesterol concentrations and the progression of atherosclerosis in guinea pigs. The guinea pig was used as the animal model for this study because of its similarities to humans in terms of hepatic cholesterol and lipoprotein metabolism. ^ The current studies demonstrate that ASBT inhibition results in increased bile acid excretion and increased hepatic bile acid biosynthesis, which was induced by a decrease in bile acid return to the liver. Cholesterol concentrations in the plasma, liver and aortic arch were significantly reduced with treatment due to this increase in bile acid synthesis. In addition, LDL and VLDL compositions were altered due to decreases in CETP activity and mRNA expression, adding to the anti-atherogenic potential of SC-435 treatment. The current studies also demonstrated that guinea pigs develop atherosclerosis on a high cholesterol diet and that this can be significantly reduced with an ASBTi monotherapy or a co-administration therapy consisting of ASBTi and simvastatin (COMBO). The COMBO therapy was the most effective treatment at reducing cholesterol concentrations in the plasma and aortic arch, demonstrating that simvastatin potentiates the activity of the ASBTi due to their complimentary mechanisms of action. From these studies, we conclude that reductions in plasma LDL-C concentrations were related to alterations in the enterohepatic circulation of bile acids by ASBT inhibition, which subsequently resulted in modulation of activity and expression of important enzymes of hepatic cholesterol homeostasis. ^