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Cholesterol and bile acid metabolism in cholesterol gallstone disease

胆固醇胆结石疾病中的胆固醇和胆汁酸代谢

基本信息

批准号：
02454226
负责人：
OSUGA Toshiaki
金额：
$ 3.46万
依托单位：
Tsukuba University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1990
资助国家：
日本
起止时间：
1990 至 1992
项目状态：
已结题

项目摘要

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.

本研究旨在阐明日本胆固醇结石患者胆固醇过饱和胆汁生成的机制。胆固醇结石患者的肝胆汁胆固醇饱和度显著高于无结石对照组。两组间肝微粒体HMG-CoA还原酶、胆固醇7 α-羟化酶和7 α-羟基-4-异戊烯-3-酮12 α-羟化酶活性无显著差异。胆固醇结石患者的胆汁酸池减少。胆汁酸合成的过度敏感的反馈抑制已经被假定来解释尺寸减小。为了阐明反馈调节中的肝脏缺陷，我们测定了患者的肝脏胆汁酸浓度。如果在我们的胆结石患者中确实存在过度敏感的反馈抑制，则可以预期肝胆汁酸浓度降低和胆固醇7 α-羟化酶活性正常或降低。但是，胆固醇结石患者的总胆酸、鹅去氧胆酸、去氧胆酸和熊去氧胆酸浓度显著高于无胆结石患者。胆结石患者肝脏中胆汁酸的蓄积不是由于肝脏胆汁酸合成增加。这可能与肝脏不能分泌胆汁酸有关。总之，我们没有发现与无结石对照组相比，日本胆固醇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可能是由胆固醇结石患者肝胆汁酸浓度的不适当增加而不是过度敏感的反馈抑制引起的。