REGULATION OF BILE ACID SYNTHESIS

胆汁酸合成的调节

• 批准号: 5210584
• 负责人: Z. R VLAHCEVIC
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5210584
• 关键词: HMG coA reductases; cholanate compound; cholesterol; dexamethasone; enzyme activity; estrogens; hydroxysteroid dehydrogenases; laboratory rat; liver cells; liver metabolism; microsomes; nucleic acid hybridization; oxygenases; steroid biosynthesis; tissue /cell culture; HMG coA reductases; cholanate compound; cholesterol; dexamethasone; enzyme activity; estrogens; hydroxysteroid dehydrogenases; laboratory rat; liver cells; liver metabolism; microsomes; nucleic acid hybridization; oxygenases; steroid biosynthesis; tissue /cell culture

Hepatic cholesterol and bile acid synthesis are coordinated, since under most physiologic and experimental conditions the activities of HMG-C0A reductase (HMG-CoA-R) and cholesterol 7alpha-hydroxylase (C7alphaH), change in tandem. Both enzymes are subject to end product feedback regulation; HMG -CoA-R by cholesterol or oxidation products of cholesterol, and C7alphaH activity by bile salts. Recent data also show that hydrophobic bile salts down-regulate HMG-CoA-R, and cholesterol feeding, up-regulates C7alphaH activities. The molecular mechanism by which HMG-CoA-R and C7alphaH are regulated by bile salts have not been fully elucidated, nor is it known how the levels of microsomal cholesterol regulate C7alphaH. Recently, we obtained specific antibodies and cDNA probes for HMG-CoA-R and C7alphaH which will enable us to study the regulation of both enzymes simultaneously. Specific questions to be addressed in this grant proposal are: 1) What is the mechanism by which bile salts and cholesterol regulate C7alphaH? 2) What is the time course and concentration dependency of repression of C7alphaH and HMG-CoA-R by naturally occurring bile salts? 3) Is down regulation of C7alphaH by cholic acid secondary to its intestinal biotransformation to deoxycholic acid? 4) Is the mechanism of regulation of HMG-CoA-R by bile salts due to direct (post- transcriptional) or indirect effects of bile salts i.e. by facilitation of intestinal cholesterol absorption? 5) What is the role of steroid hormones (estrogen, dexamethasone) in the regulation of C7alphaH? 6) Can cultured hepatocytes, prepared by new and modified methods, be used to study regulation of C7alphaH and HMG-CoA-R? In addition, in collaboration with Drs. Chiang and Hylemon, we will study the regulation of 3beta-hydroxy-delta5-C27-steroid dehydrogenase/isomerase (3beta-HSD), and 12alpha-hydroxylase (12alphaH), two key enzymes in the bile acid biosynthetic pathway. The information obtained from these studies will be relevant to our understanding of factors responsible for the regulation of C7alphaH, the key enzyme in cholesterol degradation pathway and the mechanism by which cholesterol homeostasis is maintained in the liver.

肝胆固醇和胆汁酸合成是协调的，因为 大多数生理和实验条件HMG-C0A的活性 还原酶（HMG-COA-R）和胆固醇7alpha-羟化酶（C7alphah）， 串联变化。 两种酶都有最终产品反馈 规定; HMG -COA -R胆固醇或氧化产物的HMG -COA -R 胆固醇和胆汁盐的C7alphah活性。 最近的数据也显示 疏水胆汁盐下调HMG-COA-R和胆固醇 进食，上调C7alphah活动。 分子机制 哪些HMG-COA-R和C7alphah受胆汁调节 完全阐明，也不知道微粒体的水平 胆固醇调节C7alphah。 最近，我们获得了特定的抗体 和HMG-COA-R和C7alphah的cDNA探针，这将使我们能够学习 两种酶的调节同时调节。 本赠款提案中要解决的具体问题是：1）什么是 胆汁盐和胆固醇调节C7alphah的机制？ 2） 时间过程和集中依赖的抑制依赖性 C7alphah和HMG-COA-R通过天然存在的胆汁盐？ 3）下降 通过其继发于其肠道的胆酸调节C7alphah 生物转化对脱氧胆酸？ 4）是 直接通过胆汁盐调节HMG-COA-R（ 胆汁盐的转录）或间接作用，即通过促进 肠道胆固醇吸收？ 5）类固醇的作用是什么 C7alphah调节中的激素（雌激素，地塞米松）？ 6）可以 由新方法和修改方法制备的培养的肝细胞可用于 C7alphah和HMG-COA-R的研究调节？ 另外，在 与Drs合作。清和Hylemon，我们将研究法规 3beta-Hydroxy-delta5-C27-类固醇脱氢酶/异构酶（3beta-HSD）， 和12alpha-羟化酶（12alphah），胆汁酸中的两个关键酶 生物合成途径。 从这些研究中获得的信息将 与我们对负责因素的理解有关 胆固醇降解途径中的关键酶C7alphah调节 以及胆固醇稳态平衡的机制 肝。