Cholesterol and bile acid metabolism in cholesterol gallstone disease

本研究旨在阐明日本胆固醇性胆结石患者胆固醇过饱和胆汁产生的机制。胆固醇性胆结石患者的肝胆汁胆固醇饱和度明显高于无胆结石对照组。肝微粒体HMG-CoA还原酶、胆固醇7 - α -羟化酶和7 - α -羟基-4-胆固醇-3- 1 - 12 - α -羟化酶活性在两组间无显著差异。胆固醇结石患者胆汁酸池减少。过度敏感的反馈抑制胆汁酸合成被认为是解释大小减少的原因。为了明确反馈调节中的肝缺损，我们测定了患者的肝胆汁酸浓度。如果我们的胆结石患者确实存在过度敏感的反馈抑制，那么肝胆汁酸浓度降低，胆固醇7 α -羟化酶活性正常或降低是可以预料的。然而，胆固醇结石患者的总、鹅去氧胆酸、去氧胆酸和熊去氧胆酸浓度明显高于无胆结石患者。胆结石患者肝脏中胆汁酸的积累不是由于肝胆汁酸合成的增加。这可能与肝脏不能排出胆汁酸有关。总之，我们没有发现与无结石对照相比，日本胆固醇胆结石患者肝脏胆固醇合成增加或胆汁酸合成减少的证据。然而，胆固醇7 α -羟化酶的过度反馈抑制有可能是由于胆固醇性胆结石患者肝胆汁酸浓度的不适当升高引起的，而不是由于反馈抑制过于敏感。

The present work was undertaken to clarify the mechanism of cholesterol supersaturated bile production in Japanese patients with cholesterol gallstones. The cholesterol saturation of hepatic bile was significantly higher in cholesterol gallstone patients than in gallstone-free controls. Hepatic microsomal activities of HMG-CoA reductase, cholesterol 7alpha-hydroxylase and 7alpha-hydroxy-4-cholesten-3-one 12alpha-hydroxylase did not differ significantly between the two groups. Patients with cholesterol gallstone disease have a reduced pool of bile acids. Overly sensitive feedback inhibition of bile acid synthesis has been postulated to explain the size reduction. To clarify the hepatic defect in feedback regulation, hepatic bile acid concentration was determined in our patients. If the overly sensitive feedback inhibition existed truly in our gallstone patients, decreased concentration of hepatic bile acids and normal or decreased activity of cholesterol 7alpha-hydroxylase would have been expected. However, patients with cholesterol gallstones had significantly higher total, chenodeoxycholic, deoxycholic, and ursodeoxycholic acid concentrations than patients without gallstones. The accumulation of bile acids in the liver of patients with gallstones is not due to an increased hepatic bile acid synthesis. It is probably related to the inability of the liver to excrete bile acids. In conclusion, we found no evidence of an increased hepatic cholesterol synthesis or a decreased bile acid synthesis in Japanese patients with cholesterol gallstones compared to stone-free controls. However, there is a possibility that the excessive feedback inhibition of cholesterol 7alpha-hydroxylase is induced by an inappropriate increase of hepatic bile acid concentration in cholesterol gallstone patients rather than by overly sensitive feedback inhibition.