Shefer S, Nguyen L, Salen G, Batta A K, Brooker D, Zaki F G, Rani I, Tint G S
Department of Medicine, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark 07103.
J Clin Invest. 1990 Apr;85(4):1191-8. doi: 10.1172/JCI114552.
We studied the effect of the orientation of the 7-hydroxyl group in taurocholate (7 alpha) and tauroursocholate (7 beta) on the feedback regulation of bile-acid synthesis and its rate-controlling enzyme, cholesterol 7 alpha-hydroxylase, in bile-fistula rats. To ensure a constant supply of cholesterol and to label newly synthesized bile acids, RS[2-14C]mevalonolactone was infused intraduodenally at 154 mumol/h before and during bile-acid infusion. Mevalonolactone inhibited hydroxymethyl-glutaryl CoA reductase activity 90% but did not increase bile-acid synthesis and cholesterol 7 alpha-hydroxylase activity. When sodium taurocholate was infused at the rate of 27 mumol/100 g rat per h (equivalent to the hourly hepatic bile-acid flux), bile-acid synthesis decreased 82% and cholesterol 7 alpha-hydroxylase activity declined 78%. This inhibitory effect was observed in the absence of hepatic damage. In contrast, sodium tauroursocholate infused at the same rate did not decrease bile-acid synthesis nor cholesterol 7 alpha-hydroxylase activity. Hepatic cholesterol content rose 36% with sodium taurocholate but did not change during sodium tauroursocholate administration. These results demonstrate that the feedback inhibition of bile-acid synthesis is mediated through the regulation of cholesterol 7 alpha-hydroxylase. In these experiments, taurocholate was a far more potent inhibitor than its 7 beta-hydroxy epimer, tauroursocholate.
我们研究了牛磺胆酸盐（7α）和牛磺熊去氧胆酸盐（7β）中7-羟基的方向对胆汁瘘大鼠胆汁酸合成及其速率控制酶胆固醇7α-羟化酶的反馈调节的影响。为确保胆固醇的持续供应并标记新合成的胆汁酸，在输注胆汁酸之前和期间，以154μmol/h的速率经十二指肠内输注RS[2-¹⁴C]甲羟戊酸内酯。甲羟戊酸内酯抑制羟甲基戊二酰辅酶A还原酶活性达90%，但并未增加胆汁酸合成及胆固醇7α-羟化酶活性。当以27μmol/100g大鼠·h的速率输注牛磺胆酸钠（相当于每小时肝脏胆汁酸通量）时，胆汁酸合成减少82%，胆固醇7α-羟化酶活性下降78%。在无肝损伤的情况下观察到了这种抑制作用。相比之下，以相同速率输注牛磺熊去氧胆酸钠并未降低胆汁酸合成及胆固醇7α-羟化酶活性。牛磺胆酸钠使肝脏胆固醇含量升高36%，而在输注牛磺熊去氧胆酸钠期间肝脏胆固醇含量未发生变化。这些结果表明，胆汁酸合成的反馈抑制是通过对胆固醇7α-羟化酶的调节介导的。在这些实验中，牛磺胆酸盐作为抑制剂比其7β-羟基差向异构体牛磺熊去氧胆酸盐的效力要强得多。
