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

摘要 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。通过以下方式了解基本过程 调节哪些有助于胆汁排泄的特异性转运蛋白对于改善人类健康是不可或缺的， 预测化学品暴露，并预防与化学品暴露相关的疾病。营养（即 饮食摄入，禁食和热量限制[CR]）是一个重要的因素，在易感性/进展， 各种相关疾病，特别是与衰老和环境暴露有关的疾病。反式- 白藜芦醇（RES）是红葡萄酒中的抗氧化剂，具有类似CR的抗衰老作用，并且是 脱乙酰酶Sirt 1。了解RES，禁食和CR如何调节肝脏的表达和功能 参与肝脏排泄的转运蛋白（即多药耐药相关蛋白[MRPS]）很重要 了解营养对化学品暴露和疾病有益的机制。 初步数据表明，RES增加人Mrp 1 -4，6的mRNA和蛋白表达， 肝细胞和小鼠肝脏沿着诱导受转录因子核因子- E2相关因子2（NRF 2），表明RES激活人类和小鼠NRF 2。此外，肝脏Mrp 1， 2和3的表达，沿着Ho-1的表达在禁食期间增加，其中肝cAMP增加 蛋白激酶A（PKA）被激活。此外，在KEAP 1缺失的肝脏中，NRF 2的组成性激活 小鼠导致Mrp 1 -5表达增加。该建议的假设是RES、禁食和CR 通过NRF 2介导转录的Sirt 1-和PKA-上游调节诱导MRP的表达。 具体目标将确定1）RES处理是否诱导人肝细胞中的MRP表达， 2）禁食和CR通过PKA的上游激活诱导MRP表达， Nrf 2的下游激活，3）RES、禁食和CR通过Sirt 1诱导MRP，和4）RES、禁食和CR 影响小鼠体内双酚A和多溴二苯醚的分布。总之，这些研究将确定机制， 营养状况改变人和小鼠MRPS的表达，以及证明营养是否 状态增强环境化学物质的胆汁排泄。此外，它们还将提供新颖的见解 调节人类MRP基因的NRF 2诱导的机制。项目叙述 营养状况是许多与年龄有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参与的机制， 肝脏吸收和清除体内环境化学物质的能力。

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.