LIVER/INTESTINAL METABOLISM OF BILE ACIDS AND LIPIDS

胆汁酸和脂质的肝脏/肠道代谢

• 批准号: 3095433
• 负责人: ZDRAVKO R VLAHCEVIC
• 金额: $ 86.07万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-12-01 至 1997-01-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3095433
• 关键词: cholanate compound; steroid biosynthesis

The overall objectives of this program project are to: a) broaden our understanding of the regulation of cholesterol and bile acid metabolism in the liver and in the intestines; b) define the pathway and enzymes involved in the formation of secondary bile acids by intestinal bacteria; and c) determine the mechanism by which hydrophobic bile salts cause cell injury and explore the basis for hepatoprotective action of ursodeoxycholate. The specific aims of this proposal are: 1)purification, characterization, and cloning of key enzymes in the bile acid biosynthetic pathway (cholesterol 7alpha-hydroxylase (C7alphaH), 3beta-hydroxysteroid dehydrogenase/isomerase (3beta-HSD) and 12alpha- hydroxylase (12alphaH); 2) determination of molecular basis by which bile acids, cholesterol and selected hormones regulate C7alphaH; 3) to study the regulation of 3beta-HSD and 12alphaH; 4)determine the mechanism of regulation of HMG-CoA reductase (HMG-CoA-R) by bile acids; 5) purification, characterization and cloning of hepatic cholesteryl ester hydrolase (CEH); 6) to study the regulation of CEH by bile acids, cholesterol and other regulatory agents in conjunction with other enzymes involved in the maintenance of hepatic cholesterol homeostasis; 7) purification, characterization and cloning of enzymes responsible for bacterial transformation of primary to secondary bile acids; 8) cloning and sequencing of bacterial bile acid transport (binding) protein from selected bacteria; 9) elucidation of the mechanism by which hydrophobic bile acids cause hepatic injury, and by which ursodeoxycholic acid, a representative hydrophilic bile salt protects membranes from toxic bile salts; 10) to determine the effects of different bile salts alone or in combination with UDCA, on the membrane fluidity gradient employing fluoroscopic probes to assess anisotropy at different depths within the membranes; and 11) to determine the mechanism by which hydrophobic bile salts affect cholesterol and phospholipid transfer.

这个项目的总体目标是：a)拓宽我们的