Role of Nrf2 during cholestsis and gallstone formation

描述（由申请人提供） 胆结石疾病影响超过30，000，000美国人，并且在美国每年导致超过750，000例胆囊切除术。胆结石可通过阻塞胆总管引起肝外胆汁淤积。在胆汁中，胆汁酸和磷脂对胆固醇的溶解很重要。当胆汁的组成发生变化，胆汁酸与胆固醇的比例降低（胆汁酸合成减少和/或胆固醇分泌到胆汁中增加）时，胆固醇结石形成的可能性增加。本提案的主要目的是了解转录因子核因子E2相关因子2（Nrf 2）如何调节胆汁淤积期间和暴露于高胆固醇饮食期间的胆固醇和胆汁酸代谢和处置。初步研究表明，在胆汁淤积期间，野生型（WT）小鼠和Nrf 2缺失小鼠的肝脏中肝脏转运蛋白的表达是不同的。因此，具体目标1将扩展这些初步发现，并确定在胆汁淤积期间WT和Nrf 2-null小鼠之间的药物处置是否不同。重要的是，初步研究还表明，与WT小鼠相比，Nrf 2缺失小鼠的肝脏和血清中胆汁酸水平降低，表明Nrf 2对胆汁酸合成很重要。因此，特异性目的2将确定Nrf 2调节肝脏中胆汁酸水平的机制。初步数据还表明，当暴露于高胆固醇饮食时，Nrf 2-null小鼠表现出胆固醇结石的形成增加，并且特定目标3中的研究将确定Nrf 2-null小鼠更容易形成胆结石的机制。目标3中的研究将检测胆汁胆固醇、胆汁酸和磷脂分泌，并检测胆固醇和胆汁酸合成、代谢和处置基因的肝表达差异。总之，拟议的研究将提供新的信息，肝脏调节胆固醇和胆汁酸，并提供有价值的洞察胆结石形成的发病机制。

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.