Nervi F, Bronfman M, Allalón W, Depiereux E, Del Pozo R
J Clin Invest. 1984 Dec;74(6):2226-37. doi: 10.1172/JCI111649.
Although the significance of the enterohepatic circulation of bile salts in the solubilization and biliary excretion of cholesterol is well established, little is known about the intrahepatic determinants of biliary cholesterol output. Studies were undertaken to elucidate some of these determinants in the rat. Feeding 1% diosgenin for 1 wk increased biliary cholesterol output and saturation by 400%. Bile flow, biliary bile salt, phospholipid and protein outputs remained in the normal range. When ethynyl estradiol (EE) was injected into these animals, biliary cholesterol output decreased to almost normal levels under circumstances of minor changes in the rates of biliary bile salt and phospholipid outputs. Similarly, when chylomicron cholesterol was intravenously injected into diosgenin-fed animals, biliary cholesterol output significantly decreased as a function of the dose of chylomicron cholesterol administered. Relative rates of hepatic cholesterol synthesis and esterification were measured in isolated hepatocytes. Although hepatic cholesterogenesis increased 300% in diosgenin-fed animals, the contribution of newly synthesized cholesterol to total biliary cholesterol output was only 19 +/- 9%, compared with 12 +/- 6% in control and 15 +/- 5% in diosgenin-fed and EE-injected rats. The rate of oleate incorporation into hepatocytic cholesterol esters was 30% inhibited in diosgenin-fed rats. When EE was injected into these animals, the rate of cholesterol esterification increased to almost 300%. To investigate further the interrelationship between hepatic cholesterol esterification and biliary cholesterol output, we studied 21 diosgenin-fed rats. Six of them received in addition EE and 10 received chylomicron cholesterol. The relationships between biliary cholesterol output as a function of both microsomal acyl-CoA:cholesterol acyltransferase (ACAT) activity and hepatic cholesterol ester concentration were significantly correlated in a reciprocal manner. From these results it is concluded that the size of the biliary cholesterol precursor pool can be rapidly modified through changes in the activity of the hepatic ACAT.
尽管胆汁盐的肠肝循环在胆固醇的溶解和胆汁排泄中的重要性已得到充分证实，但关于胆汁胆固醇输出的肝内决定因素却知之甚少。本研究旨在阐明大鼠体内的一些此类决定因素。喂食1%的薯蓣皂苷元1周可使胆汁胆固醇输出量和饱和度增加400%。胆汁流量、胆汁盐、磷脂和蛋白质的胆汁输出量仍在正常范围内。当向这些动物注射乙炔雌二醇（EE）时，在胆汁盐和磷脂输出率变化较小的情况下，胆汁胆固醇输出量降至几乎正常水平。同样，当向喂食薯蓣皂苷元的动物静脉注射乳糜微粒胆固醇时，胆汁胆固醇输出量会随着所给予的乳糜微粒胆固醇剂量而显著降低。在分离的肝细胞中测量了肝脏胆固醇合成和酯化的相对速率。尽管喂食薯蓣皂苷元的动物肝脏胆固醇生成增加了300%，但新合成的胆固醇对总胆汁胆固醇输出的贡献仅为19±9%，而对照组为12±6%，喂食薯蓣皂苷元并注射EE的大鼠为15±5%。在喂食薯蓣皂苷元的大鼠中，油酸掺入肝细胞胆固醇酯的速率受到30%的抑制。当向这些动物注射EE时，胆固醇酯化速率增加到几乎300%。为了进一步研究肝脏胆固醇酯化与胆汁胆固醇输出之间的相互关系，我们研究了21只喂食薯蓣皂苷元的大鼠。其中6只还接受了EE，10只接受了乳糜微粒胆固醇。胆汁胆固醇输出量与微粒体酰基辅酶A：胆固醇酰基转移酶（ACAT）活性和肝脏胆固醇酯浓度之间的关系呈显著的反比相关性。从这些结果可以得出结论，胆汁胆固醇前体池的大小可以通过肝脏ACAT活性的变化而迅速改变。
