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J. Lipid Res.
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A more recent version of this article appeared on September 1, 2003

Papers In Press, published online ahead of print June 16, 2003
J. Lipid Res., doi:10.1194/jlr.M200469-JLR200
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Submitted on December 13, 2002
Revised on May 7, 2003
Accepted on June 10, 2003

SC-435, a potent inhibitor of the Apical sodium Co-dependent bile acid transporter,reduces Atherosclerotic lesions in ApoE-/- mice

B. Ganesh Bhat, Stephen R. Rapp, Judith A. Beaudry, Nida Napawan, Dustie N. Butteiger, Kerri A. Hall, Christopher L. Null, Yi Luo, and Bradley T. Keller

Cardiovascular Research, Pfizer, Inc., Saint Louis, MO 63167

Corresponding Author: b.ganesh.bhat{at}pfizer.com

Blocking intestinal absorption of bile acids is a target for reducing plasma levels of LDL cholesterol. This can be achieved by inhibiting the ileal apical sodium co-dependent bile acid transporter (ASBT)† resulting in increased fecal bile acid excretion and accelerated hepatic utilization of cholesterol for bile acid synthesis. SC-435 was identified as a specific and potent inhibitor of ASBT, with an IC50 of 1.5 nM, in BHK cells stably transfected with the human ASBT gene. Dietary administration of 3 to 30 mg/kg SC-435 to ApoE-/- mice increased fecal bile acid excretion by more than 2.5-fold and had no significant effect on fecal neutral sterol excretion. Dietary administration of 10 mg/kg SC-435 for 12 weeks to ApoE-/- mice reduced serum total cholesterol by 35% and inhibited aortic root atherosclerotic lesion area by 65%. In agreement with the compensatory mechanism, in vivo inhibition of ileal ASBT resulted in significant increases in hepatic mRNA levels of cholesterol 7a-hydroxylase and HMG-CoA reductase. Treatment of ApoE-/- mice also resulted in decreased expressions of ileal bile acid binding protein (IBABP) and hepatic nuclear hormone receptor small heterodimer partner (SHP), direct target genes of the nuclear hormone receptor, farnesoid X receptor (FXR) suggesting a possible role of FXR in SC-435 mediated modulation of cholesterol homeostasis. SC-435 treatment in dogs reduced serum total cholesterol levels by < 15% and in combination with atorvastatin treatment, caused an additional reduction of ~25% was observed. These results suggest that specific inhibition of ASBT with SC-435 is a novel therapeutic approach for the treatment of hypercholesterolemia resulting in a decreased risk for coronary artery disease.


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