Inhibition of Ileal Na⁺/Bile Acid Cotransporter by S-8921 Reduces Serum Cholesterol and Prevents Atherosclerosis in Rabbits

From Discovery Research Laboratories II, Shionogi & Co, Ltd, Toyonaka, Osaka, Japan.

Correspondence to Seijiro Hara, PhD, Developmental Research Laboratories, Shionogi & Co, Ltd, 3-1-1, Futaba-Cho, Toyonaka, Osaka 561-0825, Japan. E-mail seijiro.hara{at}shionogi.co.jp

Abstract—The ileal Na⁺/bile acid cotransporter (IBAT) plays an important role in the enterohepatic circulation of bile acids. We investigated the effects of IBAT inhibition on the maintenance of serum cholesterol level by using a novel IBAT inhibitor, S-8921, in rabbits. Administration of S-8921 by its incorporation into the diet (0.01% to 0.1%) for 1 to 2 weeks in heterozygous Watanabe heritable hyperlipidemic rabbits decreased serum cholesterol by 29% to 37% and increased fecal excretion of measured bile acids by 60% to 180% compared with control rabbits. Liver microsomal cholesterol 7-hydroxylase and 3-hydroxy-3-methylglutaryl coenzyme A reductase activities were increased by 75% to 84% and 84% to 89%, respectively, with S-8921 treatment. S-8921 administration (0.1% in the diet) to normal New Zealand White rabbits for 2 weeks resulted in increased hepatic low density lipoprotein receptor expression, which was assessed by Northern blot analysis. In cholesterol-fed New Zealand White rabbits, S-8921 treatment (0.003% to 0.1% in the diet) for 10 weeks dose-dependently inhibited the development of hypercholesterolemia. It also inhibited the accumulation of cholesterol in the aortic arch and reduced the severity of coronary atherosclerosis. These results indicate that IBAT inhibition by S-8921 affects serum cholesterol, liver enzymes, low density lipoprotein receptor activity, and atherosclerosis in the same manner as bile acid sequestrants. We suggest that an IBAT inhibitor such as S-8921 could be useful in the treatment of hypercholesterolemia.

Key Words: ileal bile acid cotransporter • serum cholesterol • S-8921 • LDL receptor • cholesterol 7-hydroxylase

This article has been cited by other articles:

				P. A. Dawson, T. Lan, and A. Rao Bile acid transporters J. Lipid Res., December 1, 2009; 50(12): 2340 - 2357. [Abstract] [Full Text] [PDF]

				S. Sakamoto, H. Kusuhara, K. Horie, K. Takahashi, T. Baba, J. Ishizaki, and Y. Sugiyama Identification of the Transporters Involved in the Hepatobiliary Transport and Intestinal Efflux of Methyl 1-(3,4-Dimethoxyphenyl)-3-(3-ethylvaleryl)-4-hydroxy-6,7,8-trimethoxy-2-naphthoate (S-8921) Glucuronide, a Pharmacologically Active Metabolite of S-8921 Drug Metab. Dispos., August 1, 2008; 36(8): 1553 - 1561. [Abstract] [Full Text] [PDF]

				S. Sakamoto, H. Kusuhara, K. Miyata, H. Shimaoka, T. Kanazu, Y. Matsuo, K. Nomura, N. Okamura, S. Hara, K. Horie, et al. Glucuronidation Converting Methyl 1-(3,4-Dimethoxyphenyl)-3-(3-ethylvaleryl)-4-hydroxy-6,7,8-trimethoxy-2-naphthoate (S-8921) to a Potent Apical Sodium-Dependent Bile Acid Transporter Inhibitor, Resulting in a Hypocholesterolemic Action J. Pharmacol. Exp. Ther., August 1, 2007; 322(2): 610 - 618. [Abstract] [Full Text] [PDF]

				T. Claudel, B. Staels, and F. Kuipers The Farnesoid X Receptor: A Molecular Link Between Bile Acid and Lipid and Glucose Metabolism Arterioscler Thromb Vasc Biol, October 1, 2005; 25(10): 2020 - 2030. [Abstract] [Full Text] [PDF]

				B. G. Bhat, S. R. Rapp, J. A. Beaudry, N. Napawan, D. N. Butteiger, K. A. Hall, C. L. Null, Y. Luo, and B. T. Keller Inhibition of ileal bile acid transport and reduced atherosclerosis in apoE-/- mice by SC-435 J. Lipid Res., September 1, 2003; 44(9): 1614 - 1621. [Abstract] [Full Text] [PDF]

				F. Chen, L. Ma, P. A. Dawson, C. J. Sinal, E. Sehayek, F. J. Gonzalez, J. Breslow, M. Ananthanarayanan, and B. L. Shneider Liver Receptor Homologue-1 Mediates Species- and Cell Line-specific Bile Acid-dependent Negative Feedback Regulation of the Apical Sodium-dependent Bile Acid Transporter J. Biol. Chem., May 23, 2003; 278(22): 19909 - 19916. [Abstract] [Full Text] [PDF]

				M. W. Huff, D. E. Telford, J. Y. Edwards, J. R. Burnett, P. H. R. Barrett, S. R. Rapp, N. Napawan, and B. T. Keller Inhibition of the Apical Sodium-Dependent Bile Acid Transporter Reduces LDL Cholesterol and ApoB by Enhanced Plasma Clearance of LDL ApoB Arterioscler Thromb Vasc Biol, November 1, 2002; 22(11): 1884 - 1891. [Abstract] [Full Text] [PDF]

				J. Y. L. Chiang Bile Acid Regulation of Gene Expression: Roles of Nuclear Hormone Receptors Endocr. Rev., August 1, 2002; 23(4): 443 - 463. [Abstract] [Full Text] [PDF]

				F. Chen, L. Ma, N. Al-Ansari, and B. Shneider The Role of AP-1 in the Transcriptional Regulation of the Rat Apical Sodium-dependent Bile Acid Transporter J. Biol. Chem., October 12, 2001; 276(42): 38703 - 38714. [Abstract] [Full Text] [PDF]