Weis H J, Dietschy J M
J Clin Invest. 1969 Dec;48(12):2398-408. doi: 10.1172/JCI106206.
Studies were undertaken to define the role of bile acids in the control of hepatic cholesterogenesis from acetate. Both biliary diversion and biliary obstruction increase the rate of sterol synthesis by the liver 2.5- to 3-fold. After biliary diversion, however, the bile acid content of the liver is decreased, whereas after biliary obstruction, it is markedly increased. Thus, there is no relationship between the tissue content of bile acid and the rate of hepatic cholesterol synthesis. Furthermore, restoration of the enterohepatic circulation of bile acid in animals with biliary diversion fails to prevent the rise in synthetic activity seen after this manipulation. These data indicate that bile acid plays no direct inhibitory role in the regulation of cholesterol synthesis by the liver. Other experiments were therefore undertaken to evaluate the possibility that changes in cholesterogenic activity observed after manipulation of the enterohepatic circulation of bile acid actually are the result of changes in the enterolymphatic circulation of cholesterol. In support of this thesis it was found that intestinal lymphatic diversion causes the same specific enhancement of cholesterol synthetic activity as biliary diversion and that both of these operative procedures increase enzymatic activity at the step mediated by beta-hydroxy-beta-methyl glutaryl reductase. Furthermore, the increase in the rate of sterol synthesis by the liver seen in animals with biliary diversion can be prevented by the infusion of approximately 7 mg of cholesterol/24 hr in the form of chylomicrons. This is an amount of cholesterol circulating normally in the enterolymphatic circulation of the intact rat.These results indicate that bile acid plays no direct role in the control of hepatic cholesterogenesis, but rather, it is the enterohepatic circulation of endogenous cholesterol that determines directly the rate at which cholesterol is synthesized by the liver.
开展了多项研究以确定胆汁酸在控制由乙酸盐生成肝脏胆固醇过程中的作用。胆汁转流和胆管梗阻均可使肝脏中固醇合成速率提高2.5至3倍。然而，胆汁转流后，肝脏中的胆汁酸含量降低，而胆管梗阻后，胆汁酸含量则显著增加。因此，胆汁酸的组织含量与肝脏胆固醇合成速率之间并无关联。此外，在胆汁转流的动物中恢复胆汁酸的肠肝循环并不能阻止在此操作后出现的合成活性升高。这些数据表明，胆汁酸在肝脏胆固醇合成的调节中不发挥直接的抑制作用。因此开展了其他实验，以评估在对胆汁酸的肠肝循环进行操作后观察到的胆固醇生成活性变化实际上是否是胆固醇肠淋巴循环变化的结果。支持这一论点的是，发现肠道淋巴转流与胆汁转流一样会导致胆固醇合成活性出现相同的特异性增强，并且这两种手术操作都会增加由β-羟基-β-甲基戊二酰辅酶A还原酶介导步骤的酶活性。此外，通过以乳糜微粒形式每24小时输注约7毫克胆固醇，可防止胆汁转流动物中肝脏固醇合成速率的升高。这是完整大鼠肠淋巴循环中正常循环的胆固醇量。这些结果表明，胆汁酸在肝脏胆固醇生成的控制中不发挥直接作用，而是内源性胆固醇的肠肝循环直接决定了肝脏合成胆固醇的速率。
