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Journal of Lipid Research, Vol. 44, 1614-1621, September 2003
Copyright © 2003 by American Society for Biochemistry and Molecular Biology

Inhibition of ileal bile acid transport and reduced atherosclerosis in apoE^-/- mice by SC-435

B. Ganesh Bhat¹, Stephen R. Rapp, Judith A. Beaudry, Nida Napawan, Dustie N. Butteiger, Kerri A. Hall, Christopher L. Null, Yi Luo and Bradley T. Keller

Cardiovascular and Metabolic Diseases Discovery Research, Pfizer Inc., St. Louis, MO 63167

¹ To whom correspondence should be addressed. e-mail: b.ganesh.bhat{at}pfizer.com

Blocking intestinal bile acid absorption by inhibiting the apical sodium codependent bile acid transporter (ASBT) is a target for increasing hepatic bile acid synthesis and reducing plasma LDL cholesterol. SC-435 was identified as a potent inhibitor of ASBT (IC₅₀ = 1.5 nM) in cells transfected with the human ASBT gene. Dietary administration of 3 mg/kg to 30 mg/kg SC-435 to apolipoprotein E^-/- (apoE^-/-) mice increased fecal bile acid excretion by >2.5-fold. In vivo inhibition of ASBT also resulted in significant increases of hepatic mRNA levels for cholesterol 7-hydroxylase and HMG-CoA reductase. Administration of 10 mg/kg SC-435 for 12 weeks to apoE^-/- mice lowered serum total cholesterol by 35% and reduced aortic root lesion area by 65%. Treatment of apoE^-/- mice also resulted in decreased expression of ileal bile acid binding protein and hepatic nuclear hormone receptor small heterodimer partner, direct target genes of the farnesoid X receptor (FXR), suggesting a possible role of FXR in SC-435 modulation of cholesterol homeostasis. In dogs, SC-435 treatment reduced serum total cholesterol levels by 12% and, in combination with atorvastatin treatment, caused an additional reduction of 25%.

These results suggest that specific inhibition of ASBT is a novel therapeutic approach for treatment of hypercholesterolemia resulting in a decreased risk for atherosclerosis.

Abbreviations: ASBT, apical sodium codependent bile acid transporter; CAD, coronary artery disease; Cyp71, cholesterol 7-hydroxylase; FXR, farnesoid X receptor; HMGR, HMG-CoA reductase; IBABP, intestinal bile acid binding protein; SHP, small heterodimer partner

Supplementary key words apolipoprotein E • cholesterol • low density lipoprotein • apical sodium codependent bile acid transporter • farnesoid X receptor • enterohepatic

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