Xu G, Salen G, Shefer S, Ness G C, Nguyen L B, Tint G S, Parker T S, Roberts J, Batta A K, Chen T S, Zhao Z, Kong X
Medical Service, Veterans Affairs Medical Center, East Orange, NJ, USA.
Hepatology. 1996 Oct;24(4):882-7. doi: 10.1002/hep.510240421.
The effect of bile acid depletion and replacement with glycodeoxycholic acid on plasma cholesterol concentrations, hepatic low-density lipoprotein (LDL) receptor binding and messenger RNA (mRNA) levels, and hepatic activities and mRNA levels for 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and cholesterol 7alpha-hydroxylase was investigated in 19 New Zealand white (NZW) and 15 Watanabe heritable hyperlipidemic (WHHL) rabbits. Bile acid depletion was produced by external bile drainage for 5 days, which maximized cholic acid synthesis. Replacement was achieved by infusing glycodeoxycholic acid intraduodenally for 24 hours so that the hepatic bile acid flux reached prefistula levels. Plasma and liver cholesterol concentrations were 13 times and 50% greater, respectively, hepatic LDL receptor-mediated binding was 26% less, and cholesterol 7alpha-hydroxylase activity and mRNA levels were 62% and 86% less in WHHL than NZW rabbits. After bile drainage, plasma cholesterol concentrations decreased 29% in NZW rabbits and 40% in WHHL rabbits and were associated with a 2.1-fold increase in hepatic LDL receptor-mediated binding in the NZW rabbits, but there was no change in the WHHL rabbits. Cholesterol 7alpha-hydroxylase activity and mRNA levels increased three and four times in NZW and WHHL rabbits, respectively, although liver cholesterol levels remained unchanged. Replacement with exogenous glycodeoxycholic acid increased plasma cholesterol concentrations 1.7 times in NZW rabbits and decreased enhanced cholesterol 7alpha-hydroxylase activity 54%, mRNA levels 86%, cholic acid synthesis 38%, and hepatic LDL receptor-mediated binding 57% in NZW rabbits. Bile acid depletion stimulated cholic acid synthesis by up-regulating cholesterol 7alpha-hydroxylase to use cholesterol and reduce plasma concentrations substantially in both NZW and WHHL rabbits, although LDL receptors did not function in WHHL rabbits. Glycodeoxycholic acid replacement inhibited elevated cholesterol 7alpha-hydroxylase, cholic acid synthesis, and hepatic LDL receptor binding to reestablish baseline plasma cholesterol levels in NZW rabbits. Hypercholesterolemia in WHHL rabbits was related to the combination of dysfunctional LDL receptors and inhibited cholesterol 7alpha-hydroxylase. Plasma cholesterol concentrations were reduced significantly when cholesterol 7alpha-hydroxylase was stimulated even in the absence of LDL receptor function.
在19只新西兰白兔（NZW）和15只渡边遗传性高脂血症（WHHL）兔中，研究了胆汁酸耗竭并用甘氨脱氧胆酸替代对血浆胆固醇浓度、肝脏低密度脂蛋白（LDL）受体结合及信使核糖核酸（mRNA）水平，以及3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶和胆固醇7α-羟化酶的肝脏活性及mRNA水平的影响。通过体外胆汁引流5天造成胆汁酸耗竭，这使胆酸合成最大化。通过十二指肠内输注甘氨脱氧胆酸24小时实现替代，以使肝脏胆汁酸通量达到瘘管形成前的水平。与NZW兔相比，WHHL兔的血浆和肝脏胆固醇浓度分别高出13倍和50%，肝脏LDL受体介导的结合减少26%，胆固醇7α-羟化酶活性和mRNA水平分别降低62%和86%。胆汁引流后，NZW兔的血浆胆固醇浓度降低29%，WHHL兔降低40%，且NZW兔肝脏LDL受体介导的结合增加2.1倍，但WHHL兔无变化。NZW兔和WHHL兔的胆固醇7α-羟化酶活性和mRNA水平分别增加了3倍和4倍，尽管肝脏胆固醇水平保持不变。用外源性甘氨脱氧胆酸替代使NZW兔的血浆胆固醇浓度增加1.7倍，并使NZW兔增强的胆固醇7α-羟化酶活性降低54%、mRNA水平降低86%、胆酸合成降低38%、肝脏LDL受体介导的结合降低57%。胆汁酸耗竭通过上调胆固醇7α-羟化酶来利用胆固醇，从而显著降低NZW兔和WHHL兔的血浆浓度，刺激胆酸合成，尽管LDL受体在WHHL兔中不起作用。甘氨脱氧胆酸替代抑制升高的胆固醇7α-羟化酶、胆酸合成及肝脏LDL受体结合，以重建NZW兔的血浆胆固醇基线水平。WHHL兔的高胆固醇血症与LDL受体功能障碍和胆固醇7α-羟化酶受抑制的联合作用有关。即使在没有LDL受体功能的情况下，刺激胆固醇7α-羟化酶时血浆胆固醇浓度也会显著降低。
