Role of Nrf2 during cholestsis and gallstone formation

Nrf2 在胆汁淤积和胆结石形成过程中的作用

• 批准号: 6926783
• 负责人: Angela L Slitt
• 金额: $ 10.76万
• 依托单位: UNIVERSITY OF RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-22 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6926783
• 关键词: Affect; American; Anions; Antioxidants; Bile Acid Biosynthesis Pathway; Bile Acids; Bile fluid; Biliary; Biliary calculi; Bilirubin; Blood; Caspase-1; Chemicals; Cholecystectomy; Cholelithiasis; Cholestasis; Cholesterol; Cholesterol Homeostasis; Clinical; Common bile duct structure; Condition; Data; Development; Diet; Disease; Excretory function; Exhibits; Exposure to; Extrahepatic Cholestasis; Family; Frequencies; Future; Gene Expression; Genes; Goals; Grant; Heme; Hepatic; Hepatocyte; Human; Investigation; Knockout Mice; Ligation; Liver; Mediating; Metabolism; Modeling; Molecular; Mouse Strains; Multidrug Resistance-Associated Proteins; Mus; NAD(P)H dehydrogenase (quinone) 1, human; NF-E2-related factor 2; Nuclear; OATP Transporters; Oxidative Stress; Oxygenases; P-Glycoproteins; Pathogenesis; Pharmaceutical Preparations; Phase; Phospholipids; Pilot Projects; Population; Predisposition; Probability; Regulation; Reporting; Research Personnel; Resistance; Role; Serum; Sex Characteristics; Single Nucleotide Polymorphism; Thinking; Transcriptional Activation; Transcriptional Regulation; Transferase; United States; Wild Type Mouse; Xenobiotics; bZIP Domain; base; bile duct; feeding; insight; mRNA Expression; novel; oltipraz; prevent; programs; protein expression; transcription factor; uptake

DESCRIPTION (provided by applicant) Gallstone disease affects more than 30,000,000 Americans and results in more than 750,000 cholecystectomies in the United States annually. Gallstones can cause extrahepatic cholestasis by occluding the common bile duct. In bile, bile acids and phospholipids are important for the solubilization of cholesterol. When the composition of bile changes such that the ratio of bile acids to cholesterol decreases (either decreased bile acid synthesis and/or increased cholesterol secretion into bile), the probability for formation of cholesterol gallstones increases. The broad objective of this proposal is to understand how the transcription factor Nuclear Factor-E2-related factor 2 (Nrf2) regulates cholesterol and bile acid metabolism and disposition during cholestasis and during exposure to a high cholesterol diet. Preliminary studies show that liver transporter expression is different in livers from wild-type (WT) mice and Nrf2-null mice during cholestasis. Thus, Specific Aim 1 will expand upon these initial findings and determine whether drug disposition differs between WT and Nrf2-null mice during cholestasis. Importantly, preliminary studies also demonstrated that bile acid levels are decreased in liver and serum from Nrf2-null mice as compared to WT mice, suggesting that Nrf2 is important for bile acid synthesis. Therefore, Specific Aim 2 will determine the mechanism by which Nrf2 regulates bile acid levels in liver. Preliminary data also indicated that Nrf2-null mice exhibit increased formation of cholesterol gallstones when exposed to a high cholesterol diet, and studies in Specific Aim 3 will determine the mechanism by which Nrf2-null mice are more susceptible to gallstone formation. Studies in aim 3 will examine biliary cholesterol, bile acid, and phospholipid secretion as well as examine differences in heptic expression of genes for cholesterol and bile acid synthesis, metabolism, and disposition. Together, the proposed studies will provide novel information regarding liver regulation of cholesterol and bile acids and provide valuable insight into the pathogenesis of gallstone formation.

描述（由申请人提供） 胆结石疾病会影响3万多名美国人，每年在美国导致超过750,000个胆囊切除术。胆结石可以通过遮挡普通胆管引起肝外胆汁淤积。在胆汁中，胆汁酸和磷脂对于胆固醇的溶解很重要。当胆汁的组成变化使胆汁酸与胆固醇的比率降低（胆汁酸合成降低和/或增加胆固醇分泌成胆汁）时，形成胆固醇胆结石的可能性会增加。该提案的广泛目的是了解转录因子核因子与E2相关因子2（NRF2）如何调节胆固醇和胆汁酸代谢和胆汁酸代谢以及在暴露于高胆固醇饮食期间的胆固醇。初步研究表明，胆汁淤积过程中野生型（WT）小鼠和N​​RF2-NULL小鼠的肝脏转运蛋白表达不同。因此，具体的目标1将在这些初始发现上扩展，并确定胆汁淤积过程中WT和NRF2-NULL小鼠之间的药物处置是否有所不同。重要的是，初步研究还表明，与WT小鼠相比，NRF2-NULL小鼠的肝脏和血清中胆汁酸水平降低，这表明NRF2对于胆汁酸合成很重要。因此，特定的目标2将确定NRF2调节肝脏中胆汁酸水平的机制。初步数据还表明，在暴露于高胆固醇饮食的情况下，NRF2-NULL小鼠在胆固醇胆结石的形成增加增加，并且在特定目标3中的研究将确定NRF2-NULL小鼠更容易形成胆结石的机制。 AIM 3中的研究将检查胆固醇，胆汁酸和磷脂分泌，并检查胆固醇和胆汁酸合成，代谢和处置的基因的甲基表达差异。拟议的研究将共同​​提供有关胆固醇和胆汁酸的肝脏调节的新信息，并为胆结石形成的发病机理提供宝贵的见解。