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

摘要 肝脏胆汁排泄是帮助消除外来化学物质的基本过程， 并保护身体免受化学物质和毒物的积聚。通过以下方式了解基本流程 哪些有助于胆汁排泄的特定转运蛋白受到调控，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 饮食摄入量、禁食和卡路里限制[CR])是高血压易感性/进展的重要因素 各种相关疾病，尤指那些与衰老和环境暴露有关的疾病。转接- 白藜芦醇(Res)是红葡萄酒中的一种抗氧化剂，具有模拟CR的抗衰老作用，是一种 脱乙酰酶Sirt1。了解RES、空腹和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)很重要 了解营养有益于预防化学物质暴露和疾病的机制。 初步研究表明，白藜芦醇可增加人MRp1-4、6的mRNA和蛋白表达 肝细胞和小鼠肝脏以及转录因子核因子调控基因的诱导- E2相关因子2(NRF2)，提示RES能激活人和小鼠的NRF2。此外，肝脏MR_1， 2和3的表达，以及HO-1的表达在禁食过程中增加，其中肝脏cAMP增加 蛋白激酶A(PKA)被激活。此外，NRF2在Keap1-空的肝脏中的结构性激活 小鼠导致mrp1-5表达增加。该建议的假设是RES、Fasting和CR 通过Sirt1和PKA上游调控NRF2介导的转录诱导MRPs的表达。 特定的目的将决定1)RES处理是否诱导人肝细胞MRP的表达和 2)禁食和CR通过上调PKA和CR的激活诱导MRP的表达 NRF2、3)RES、空腹和CR的下游激活通过Sirt1和4)RES、空腹和CR诱导MRP 影响小鼠对双酚A和多溴联苯醚的处置。总而言之，这些研究将定义 营养状态改变人和小鼠MRPS的表达，以及证明营养是否 这种状况会增加胆道中环境化学物质的排泄。此外，它们还将提供新的见解 研究了调控NRF2诱导人类MRP基因的机制。项目叙事 营养状况是许多与年龄相关的疾病发展的重要因素。一些人 环境化学品被认为会加剧或促进年龄的发展/进步- 相关疾病。该项目的目的是确定营养是否影响参与 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.