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

基本信息

批准号：
7540194
负责人：
Angela L Slitt
金额：
$ 47.78万
依托单位：
UNIVERSITY OF RHODE ISLAND
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-08 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7540194
关键词：
ABCC1 gene Address Affect Aging Agonist Antioxidants Bile fluid Biliary Blood Blood Glucose Caloric Restriction Cells Chemical Exposure Chemicals Condition 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 Numbers Nutrient Nutritional status Pathway interactions Peroxisome Proliferators Pilot Projects Plastics Predisposition Process Production Property Proteins Purpose Rate Rattus Regulation Reporter Resveratrol Risk S cerevisiae MRP2 protein Small Interfering RNA Thinking Transgenic Organisms Up-Regulation Urine Viral Western Blotting Yeasts age effect age related anti aging bisphenol A deprivation environmental chemical feeding gene induction glucose production glucuronide improved in vivo insight liver function mRNA Expression novel nutrition phenyl ether pollutant prevent protein expression red wine toxicant trans-resveratrol transcription factor uptake urinary

项目摘要

DESCRIPTION (provided by applicant) 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 upstream 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 polybrominated diphenyl ethers (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.

描述（由申请人提供）肝胆汁排泄是一个重要的过程，有助于消除外来化学物质，并保护身体免受化学物质和有毒物质的积累。了解有助于胆汁排泄的特定转运蛋白受到调节的基本过程对于改善人类健康、预测化学品暴露和预防与化学品暴露相关的疾病至关重要。营养（即膳食摄入、禁食和热量限制 [CR]）是多种相关疾病（尤其是与衰老和环境暴露相关的疾病）易感性/进展的重要因素。反式白藜芦醇 (RES) 是红酒中的一种抗氧化剂，具有与 CR 类似的抗衰老作用，并且是脱乙酰酶 Sirt1 的激动剂。了解 RES、禁食和 CR 如何调节参与肝脏排泄的肝脏转运蛋白（即多药耐药相关蛋白 [MRP]）的表达和功能，对于了解营养有益于预防化学物质暴露和疾病的机制非常重要。初步数据表明，RES 增加人肝细胞和小鼠肝脏中 Mrp1-4、6 的 mRNA 和蛋白表达，同时诱导受转录因子核因子 E2 相关因子 2 (NRF2) 调节的基因，表明 RES 激活人类肝细胞中的 Mrp1-4、6 的 mRNA 和蛋白表达。和小鼠 NRF2。此外，禁食期间肝脏 Mrp1、2 和 3 表达以及 Ho-1 表达增加，此时肝脏 cAMP 增加并且蛋白激酶 A (PKA) 被激活。此外，KEAP1 缺失小鼠肝脏中 NRF2 的组成型激活导致 Mrp1-5 表达增加。该提议的假设是RES、禁食和CR通过NRF2介导的转录的Sirt1和PKA上游调节诱导MRP的表达。具体目标将确定 1) RES 治疗是否通过 NRF2 诱导人肝细胞和小鼠肝脏中的 MRP 表达，2) 禁食和 CR 通过上游激活 PKA 和下游激活 Nrf2 诱导 MRP 表达，3) RES、禁食和 CR 诱导 MRP通过 Sirt1 和 4) RES、禁食和 CR 影响小鼠体内双酚 A 和多溴二苯醚 (PBDE) 的处置。这些研究将共同确定营养状况改变人类和小鼠 MRPS 表达的机制，并证明营养状况是否会增强环境化学物质的胆汁排泄。此外，他们还将为调节人类 MRP 基因 NRF2 诱导的机制提供新的见解。项目叙述营养状况是许多与年龄相关的疾病发生的重要因素。一些环境化学物质被认为会加剧或促进与年龄相关的疾病的发生/进展。该项目的目的是确定营养是否影响肝脏吸收和清除体内环境化学物质的能力的机制。