Effect of nutritional status on MRP2 expression and biliary excretion of bispheno

营养状况对MRP2表达和双酚胆汁排泄的影响

• 批准号: 7847889
• 负责人: Angela L Slitt
• 金额: $ 11.87万
• 依托单位: UNIVERSITY OF RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-08 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7847889
• 关键词: Address; Affect; Aging; Agonist; Antioxidants; Bile fluid; Biliary; Blood; Blood Glucose; Caloric Restriction; Cells; Chemical Exposure; Chemicals; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Data Analyses; Deacetylase; Development; Diet; Diet Modification; Dietary intake; Disease; Dose; Endocrine disruption; Environmental Exposure; Enzymes; Ethnic Origin; Excretory function; Exposure to; Fasting; Food; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Glucagon; Gluconeogenesis; Glucose; Glucuronides; Health; Hepatic; Hepatocyte; Human; Knockout Mice; Life Style; Liver; Longevity; Measures; Mediating; Messenger RNA; Metabolic; Multidrug Resistance-Associated Proteins; Mus; Nuclear; Nutrient; Nutritional status; Pathway interactions; Peroxisome Proliferators; Pilot Projects; Plastics; Predisposition; Process; Production; Property; Proteins; Rattus; Regulation; Reporter; Resveratrol; Risk; S cerevisiae MRP2 protein; Small Interfering RNA; Transgenic Organisms; Up-Regulation; Urine; Viral; Western Blotting; Yeasts; abstracting; age effect; age related; anti aging; bisphenol A; deprivation; environmental chemical; feeding; gene induction; glucose production; improved; in vivo; insight; liver function; mRNA Expression; novel; nutrition; pentabromodiphenyl ether; pollutant; prevent; protein expression; red wine; toxicant; trans-resveratrol; transcription factor; uptake; urinary

Abstract Hepatic biliary excretion is an essential process that exists to aid the in the elimination of foreign chemicals, and protects the body from accumulating chemicals and toxicants. Understanding the underlying processes by which specific transporters that aid in biliary excretion are regulated is integral for improving human health, predicting chemical exposure, and preventing disease associated with chemical exposure. Nutrition (i.e. dietary intake, fasting, and caloric restriction [CR]) is an important factor in the susceptibility/progression of a variety of diseases associated, especially those associated with aging and environmental exposure. Trans- resveratrol (RES) is an antioxidant in red wine with anti-aging effects that mimic CR, and is an agonist for the deacetylase Sirt1. Understanding how RES, fasting, and CR regulate the expression and function of liver transporters involved in hepatic excretion (i.e. Multidrug Resistance-Associated Proteins [MRPS]) is important for understanding mechanisms by which nutrition is beneficial against chemical exposure and disease. Preliminary data demonstrates that RES increases the mRNA and protein expression of Mrp1-4, 6 in human hepatocytes and mouse liver along with induction of genes regulated by the transcription factor Nuclear Factor- E2-Related Factor 2 (NRF2), suggesting that RES activates human and mouse NRF2. Additionally, liver Mrp1, 2, and 3 expression, along with Ho-1 expression is increased during fasting, in which liver cAMP is increased and Protein Kinase A (PKA) is activated. Furthermore, constitutive activation of NRF2 in livers of KEAP1-null mice results in increased Mrp1-5 expression. The hypothesis of this proposal is that RES, fasting, and CR induce expression of MRPs through Sirt1- and PKA- upstream regulation of NRF2-mediated transcription. Specific aims will determine whether 1) RES treatment induces MRP expression in human hepatocytes and mouse liver through NRF2, 2) fasting and CR induce MRP expression via uptream activation of PKA and downstream activation of Nrf2, 3) RES, fasting, and CR induce MRP via Sirt1, and 4) RES, fasting, and CR affect bisphenol A and PBDE disposition in mice. Together, these studies will define mechanisms by which nutritional status alters expression of human and mouse MRPS, as well as demonstrate whether nutritional status enhances biliary excretion of environmental chemicals. Moreover, they will also provide novel insights into mechanisms that regulate NRF2-induction of human MRP genes. Project Narrative Nutritional status is an important factor for the development of many age-related diseases. Some environmental chemicals are thought to exacerbate or contribute to the development/progression of age- related diseases. The purpose of this project is to determine whether nutrition affects mechanisms involved in the liver's ability to uptake and clear environmental chemicals from the body.

抽象的 肝胆道排泄是一个重要的过程，它有助于消除外国化学物质， 并保护人体免于积累化学物质和有毒物质。了解基础过程 哪些有助于胆汁排泄的特定转运蛋白受到调节是改善人类健康不可或缺的一部分， 预测化学暴露，并预防与化学暴露有关的疾病。营养（即 饮食摄入，禁食和热量限制[CR]）是易感性/进展的重要因素 各种各样的疾病，尤其是与衰老和环境暴露有关的疾病。译 白藜芦醇（RES）是红酒中的抗氧化剂，具有模仿Cr的抗衰老作用，并且是抗衰老效果 脱乙酰基酶SIRT1。了解RES，禁食和CR如何调节肝脏的表达和功能 参与肝排泄的转运蛋白（即多药抗性相关蛋白[MRPS]）很重要 为了理解营养对化学暴露和疾病有益的机制。 初步数据表明，RES在人类中增加了MRP1-4、6的mRNA和蛋白质表达 肝细胞和小鼠肝脏以及由转录因子核因子调节的基因 - E2相关因子2（NRF2），表明RES激活了人和小鼠NRF2。此外，肝脏MRP1， 在禁食期间，2和3表达以及HO-1表达增加，其中肝营地增加了 和蛋白激酶A（PKA）被激活。此外，Keap1-Null肝脏中NRF2的本构激活 小鼠导致MRP1-5表达增加。该提议的假设是RES，禁食和CR 通过SIRT1和PKA-上游调节NRF2介导的转录诱导MRP的表达。 具体目的将确定1）RES治疗是否在人肝细胞中诱导MRP表达和 通过NRF2的小鼠肝脏，2）禁食和CR通过PKA上游激活和CR诱导MRP表达 NRF2、3）RES，禁食和CR的下游激活通过SIRT1诱导MRP，4）RES，禁食和CR 影响小鼠双酚A和PBDE处置。这些研究将共同​​定义机制 营养状况改变了人类和小鼠MRP的表达，并证明了营养是否是否营养 状态增强了环境化学物质的胆汁排泄。而且，他们还将提供新颖的见解 进入调节人类MRP基因NRF2诱导的机制。项目叙述 营养状况是发展许多与年龄相关疾病的重要因素。一些 环境化学物质被认为会加剧或有助于年龄的发展/进展 相关疾病。该项目的目的是确定营养是否影响涉及的机制 肝脏从体内吸收和清除环境化学物质的能力。