Huff Murray W, Telford Dawn E, Edwards Jane Y, Burnett John R, Barrett P Hugh R, Rapp Stephen R, Napawan Nida, Keller Bradley T
Department of Medicine and Biochemistry and The John P. Robarts Research Institute, The University of Western Ontario, London, Ontario, Canada.
Arterioscler Thromb Vasc Biol. 2002 Nov 1;22(11):1884-91. doi: 10.1161/01.atv.0000035390.87288.26.
Cloning of the ileal apical sodium-dependent bile acid transporter (ASBT) has identified a new pharmacological target for the modulation of plasma lipoproteins. The objective of this study was to determine whether a novel, specific, minimally absorbed ASBT inhibitor (SC-435) decreases LDL cholesterol through the alteration of plasma apoB kinetics.
Miniature pigs were treated for 21 days with 10 mg/kg/day of SC-435 or placebo. SC-435 decreased plasma cholesterol by 9% and LDL cholesterol by 20% with no effect on other lipids. Autologous (131)I-VLDL, (125)I-LDL, and [(3)H]-leucine were injected simultaneously to determine apoB kinetics. LDL apoB concentrations decreased significantly by 10% resulting entirely from an increase in LDL-apoB fractional catabolic rate. SC-435 had no effect on either total LDL apoB production or VLDL apoB converted to LDL. SC-435 increased VLDL apoB production by 22%; however, the concentration was unchanged as a result of increased VLDL apoB direct removal. SC-435 increased hepatic mRNA and enzymatic activity for both cholesterol 7alpha-hydroxylase and HMG-CoA reductase. Hepatic LDL receptor mRNA increased significantly, whereas apoB expression was unaffected.
A low dose of the ASBT inhibitor, SC-435, significantly reduces plasma LDL cholesterol through enhanced LDL receptor-mediated LDL apoB clearance, secondary to increased expression of cholesterol 7alpha-hydroxylase.
回肠顶端钠依赖性胆汁酸转运蛋白（ASBT）的克隆确定了一个调节血浆脂蛋白的新药理学靶点。本研究的目的是确定一种新型、特异性、低吸收的ASBT抑制剂（SC-435）是否通过改变血浆载脂蛋白B动力学来降低低密度脂蛋白胆固醇。
小型猪用10mg/kg/天的SC-435或安慰剂治疗21天。SC-435使血浆胆固醇降低9%，低密度脂蛋白胆固醇降低20%，对其他脂质无影响。同时注射自体（131）I-VLDL、（125）I-LDL和[（3）H]-亮氨酸以确定载脂蛋白B动力学。低密度脂蛋白载脂蛋白B浓度显著降低10%，这完全是由于低密度脂蛋白-载脂蛋白B分数分解代谢率增加所致。SC-435对总低密度脂蛋白载脂蛋白B产生或转化为低密度脂蛋白的极低密度脂蛋白载脂蛋白B均无影响。SC-435使极低密度脂蛋白载脂蛋白B产生增加22%；然而，由于极低密度脂蛋白载脂蛋白B直接清除增加，其浓度未改变。SC-435增加了胆固醇7α-羟化酶和HMG-CoA还原酶的肝脏mRNA和酶活性。肝脏低密度脂蛋白受体mRNA显著增加，而载脂蛋白B表达未受影响。
低剂量的ASBT抑制剂SC-435通过增强低密度脂蛋白受体介导的低密度脂蛋白载脂蛋白B清除，继发于胆固醇7α-羟化酶表达增加，显著降低血浆低密度脂蛋白胆固醇。
