Stone B G, Erickson S K, Craig W Y, Cooper A D
J Clin Invest. 1985 Nov;76(5):1773-81. doi: 10.1172/JCI112168.
Propensity for cholesterol gallstone formation is determined in part by biliary cholesterol content relative to bile salts and phospholipid. We examined the hypothesis that the rate of biliary cholesterol secretion can be controlled by availability of an hepatic metabolically active free cholesterol pool whose size is determined in part by rates of sterol synthesis, as reflected by activity of the primary rate-limiting enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase and of sterol esterification, as reflected by the activity of the enzyme acyl coenzyme A/cholesterol acyltransferase (ACAT). Rats were prepared with biliary, venous, and duodenal catheters. The enterohepatic circulation of biliary lipids was maintained constant by infusion of a bile salt, lecithin, cholesterol replacement solution. Administration of 25-hydroxycholesterol decreased HMG CoA reductase activity, increased ACAT activity, and decreased biliary cholesterol output 26% by 1 h. By 2 h, ACAT activity and biliary cholesterol secretion were at control levels. Administration of mevinolin, a competitive inhibitor of HMG CoA reductase, had no effect on ACAT activity and decreased biliary cholesterol secretion 16%. Administration of progesterone, an inhibitor of ACAT, had no effect on HMG CoA reductase and increased biliary cholesterol output 32% at 1 h. By 2 h, all parameters were near control levels. None of these agents had any significant effect on biliary bile salt or phospholipid secretion. Thus, acutely altering rates of esterification and/or synthesis can have profound effects on biliary cholesterol secretion independent of the other biliary lipids. These experiments suggest the existence of a metabolically active pool of free cholesterol that serves as a precursor pool for biliary cholesterol secretion. Furthermore, the size of this precursor pool is determined in part both by rates of cholesterol synthesis and esterification and is a key determinant of biliary cholesterol secretion.
胆固醇胆结石形成的倾向部分取决于胆汁中胆固醇含量与胆汁盐和磷脂的相对比例。我们检验了这样一个假说：胆汁中胆固醇的分泌速率可由肝脏中具有代谢活性的游离胆固醇池的可用性来控制，该池的大小部分由甾醇合成速率决定，这可通过主要限速酶3-羟基-3-甲基戊二酰辅酶A（HMG CoA）还原酶的活性反映出来；还由甾醇酯化速率决定，这可通过酰基辅酶A/胆固醇酰基转移酶（ACAT）的活性反映出来。给大鼠插入胆管、静脉和十二指肠导管。通过输注胆汁盐、卵磷脂、胆固醇替代溶液，维持胆汁脂质的肠肝循环恒定。给予25-羟基胆固醇可降低HMG CoA还原酶活性，增加ACAT活性，并在1小时内使胆汁胆固醇输出量降低26%。到2小时时，ACAT活性和胆汁胆固醇分泌恢复到对照水平。给予美伐他汀（一种HMG CoA还原酶的竞争性抑制剂）对ACAT活性无影响，但可使胆汁胆固醇分泌降低16%。给予孕酮（一种ACAT抑制剂）对HMG CoA还原酶无影响，并在1小时时使胆汁胆固醇输出量增加32%。到2小时时，所有参数均接近对照水平。这些药物均未对胆汁盐或磷脂分泌产生任何显著影响。因此，急性改变酯化和/或合成速率可对胆汁胆固醇分泌产生深远影响，而与其他胆汁脂质无关。这些实验表明存在一个具有代谢活性的游离胆固醇池，它作为胆汁胆固醇分泌的前体池。此外，这个前体池的大小部分由胆固醇合成和酯化速率决定，并且是胆汁胆固醇分泌的关键决定因素。
