No 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...

No abstract