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

描述(由申请人提供) 肝脏胆汁排泄是帮助人体排出外来化学物质，保护身体免受化学物质和毒物积聚的基本过程。了解帮助胆汁排泄的特定转运蛋白被调控的潜在过程对于改善人类健康、预测化学物质暴露和预防与化学物质暴露相关的疾病是不可或缺的。营养(即饮食摄入量、禁食和卡路里限制[CR])是各种相关疾病的易感性/进展的重要因素，尤其是与衰老和环境暴露相关的疾病。反式白藜芦醇(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，是脱乙酰酶Sirt1的激动剂。了解RES、空腹和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(MRPs))的表达和功能，对于了解营养有助于抵御化学暴露和疾病的机制非常重要。初步数据表明，Res可增加人肝细胞和小鼠肝脏中MRp1-4、6的mRNA和蛋白表达，并诱导转录因子核因子-E2相关因子2(NRF2)调控的基因表达，提示Res可激活人和小鼠的NRF2。此外，在禁食过程中，肝脏mRp1、2和3的表达以及HO-1的表达增加，其中肝脏cAMP增加，蛋白激酶A(PKA)被激活。此外，Keap1基因缺失小鼠肝脏中NRF2的结构性激活导致了mrp1-5表达的增加。这一设想的假设是，RES、空腹和CR通过Sirt1和PKA上游调控NRF2介导的转录来诱导MRPs的表达。特异性靶点将决定1)RES处理是否通过NRF2诱导人肝细胞和小鼠肝脏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、空腹和CR通过Sirt1诱导MRP，以及4)RES、空腹和CR影响小鼠双酚A和多溴二苯醚(PBDE)的处置。总之，这些研究将确定营养状况改变人和小鼠MRP表达的机制，并证明营养状况是否会增加环境化学物质的胆汁排泄。此外，他们还将为调节NRF2诱导人类MRP基因的机制提供新的见解。 项目叙述营养状况是许多年龄相关疾病发生的重要因素。一些环境化学品被认为会加剧或促进与年龄有关的疾病的发展/进展。这个项目的目的是确定营养是否影响肝脏从体内吸收和清除环境化学物质的能力所涉及的机制。

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.