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

Abstract

Abstract-The ileal Naϩ /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. (Arterioscler Thromb Vasc Biol. 1998;18:1304-1311.) Key Words: ileal bile acid cotransporter Ⅲ serum cholesterol Ⅲ S-8921 Ⅲ LDL receptor Ⅲ cholesterol 7␣-hydroxylase H ypercholesterolemia has been recognized as a major risk factor for coronary heart disease (CHD). In clinical trials, reducing serum LDL cholesterol has been demonstrated to decrease the incidence of CHD and to reverse atherosclerotic lesions.1-4 Two main classes of clinically useful hypocholesterolemic agents are the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors and the bile acid sequestrants. Both induce hepatic LDL receptor activity by increasing hepatic cholesterol demand. [5][6][7][8] Because the major determinant of serum cholesterol level is hepatic LDL receptor activity, 9 these agents share a common mechanism leading to reduction of cholesterol.In the case of bile acid sequestrants such as cholestyramine and colestipol, they are nonspecific anion-exchange resins, and patients have complained of their bulkiness. 10 The mechanism of action of a bile acid sequestrant is to inhibit the enterohepatic circulation of bile acids. Bile acids are synthesized from cholesterol in the liver and secreted into the bile flow to facilitate the digestion and absorption of lipids, followed by nearly quantitative reabsorption from the intestine. 11 The ileal Na ϩ /bile acid cotransporter (IBAT) maintains the reabsorption of bile acids from the intestine, 12,13 and thus, its inhibitor is expected...

The solute carrier family SLC10: more than a family of bile acid transporters regarding function and phylogenetic relationships

“…Similarly, several specific ASBT inhibitors were able to significantly lower plasma cholesterol levels and/or prevent atherosclerosis in animal studies, supporting the feasibility of a cholesterol-lowering therapy by blocking the ASBT transport function Higaki et al 1998;Ichihashi et al 1998;West et al 2002;Li et al 2004;Tremont et al 2005). Several classes of ASBT inhibitors were developed (see Fig.…”

“…The strongest compound in this group is S 8921 6 , which is a mixed competitive and non-competitive ASBT inhibitor with an IC 50 value of 2.5 μM (Hara et al 1997;Tollefson et al 2000). In vivo studies with S 8921 were performed in hamsters, rats and rabbits and revealed an upregulation of the cholesterol 7α-hydroxylase and HMG-CoA reductase activities, an increase in the hepatic LDL-receptor expression concomitant with reduced plasma cholesterol levels (Higaki et al 1998;Ichihashi et al 1998). Furthermore, in cholesterol-fed New Zealand White rabbits, S 8921 treatment efficiently suppressed the development of hypercholesterolaemia and reduced the severity of coronary atherosclerosis (Higaki et al 1998).…”

“…In vivo studies with S 8921 were performed in hamsters, rats and rabbits and revealed an upregulation of the cholesterol 7α-hydroxylase and HMG-CoA reductase activities, an increase in the hepatic LDL-receptor expression concomitant with reduced plasma cholesterol levels (Higaki et al 1998;Ichihashi et al 1998). Furthermore, in cholesterol-fed New Zealand White rabbits, S 8921 treatment efficiently suppressed the development of hypercholesterolaemia and reduced the severity of coronary atherosclerosis (Higaki et al 1998). Finally, a fourth class of 4-oxo-1-phenyl-1,4-dihydroquinoline-based ASBT in-hibitors was developed.…”

Treating hypercholesterolemia: Looking forward

“…44 S-8921, a bile acid transport inhibitor that entered phase I clinical trials in 2000, has been shown in preclinical studies to reduce serum cholesterol levels via mechanisms that may involve increased fecal excretion of bile acids and increased hepatic LDL receptor expression. 45,46 Animal data also indicate a decrease in the appearance of severe stenosis with S-8921. 46 Like cholesterol absorption inhibitors such as ezetimibe, the bile acid transport inhibitors could potentially be used with statin therapy to improve cholesterol lowering.…”

“…45,46 Animal data also indicate a decrease in the appearance of severe stenosis with S-8921. 46 Like cholesterol absorption inhibitors such as ezetimibe, the bile acid transport inhibitors could potentially be used with statin therapy to improve cholesterol lowering. 44 Three more experimental agents are members of a class known as acyl CoA:cholesterol acyltransferase (ACAT) inhibitors.…”