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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：
8282836
负责人：
Angela L Slitt
金额：
$ 36.17万
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 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8282836
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 Environmental Pollutants 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 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 prevent protein expression red wine toxicant trans-resveratrol transcription factor uptake urinary

项目摘要

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.

摘要