Crosstalk between estrogen and bile acid signaling pathway

雌激素和胆汁酸信号通路之间的串扰

• 批准号: 8586795
• 负责人: Ruitang Deng
• 金额: $ 0.14万
• 依托单位: UNIVERSITY OF RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-15 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8586795
• 关键词: Animal Model; Bile Acids; Bile Acids and Salts; Bile fluid; Biliary; Biological; Blood Circulation; Cardiovascular system; Chimera organism; Cholelithiasis; Cholestasis; Cholesterol; Detergents; Development; Disease; Down-Regulation; Endocrine Glands; Enterohepatic Circulation; Estrogen Nuclear Receptor; Estrogen Receptor 1; Estrogen Receptors; Estrogens; Exhibits; Female; Fluorescence; Gene Targeting; Gonadal Steroid Hormones; Hepatic; Hepatocyte; Homeostasis; Human; Imaging technology; In Vitro; Intrahepatic Cholestasis; Life; Limes; Link; Lipids; Liver; Liver diseases; Maintenance; Maps; Mediating; Molecular; Mus; Nuclear Receptors; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Physiological; Play; Precipitation; Pregnancy; Production; Pump; Receptor Signaling; Recombinants; Repression; Risk Factors; Role; Sex Functioning; Signal Pathway; Signaling Molecule; Subfamily lentivirinae; Testing; Therapeutic Agents; Third Pregnancy Trimester; Time; Transactivation; Woman; base; bile salts; blood glucose regulation; body system; design; farnesoid X-activated receptor; gender preference; in vivo; insight; intrahepatic; intrahepatic cholestasis of pregnancy; man; novel; prevent; promoter; public health relevance; receptor; reproductive function; research study; response

DESCRIPTION (provided by applicant): In addition to the well-known roles in development and maintenance of normal sexual and reproductive function, estrogen exerts a vast range of biological effects in nonclassical endocrine organ systems, such as cardiovascular system and liver. Bile acids are metabolites of cholesterol and have been identified as a class of signaling molecules for nuclear receptor farnesoid X receptor (FXR). Activation of FXR by bile acids regulates a myriad of FXR target genes involving in maintenance of bile acids, cholesterol, lipids and glucose homeostasis. Bile acid salt export pump (BSEP) positively regulated by bile acids through activating FXR plays a critical role in maintaining bile acid homeostasis in the liver and bile as a canalicular bile acid effluxer. Among diseases resulted from imbalance of bile acid levels, intrahepatic cholestasis of pregnancy (ICP) and gallstone disease are both associated with sex hormone estrogen. Although multiple risk factors are linked to those disorders, studies have demonstrated that estrogen plays a key role in the induction of the diseases. Both estrogen-induced cholestasis and gallstone disease have been reproduced in animal model. However, our understanding on the underlying mechanisms is far from complete. In our preliminary study, we found that estrogen repressed human BSEP expression in vitro and in vivo, and the repression was mediated by estrogen receptor 1 (ER1) through physically interacting with FXR, indicating a crosstalk between estrogen/ER1 and bile acids/FXR signaling pathway. The central hypothesis to be tested is that down-regulation of BSEP expression by estrogen is mediated through a novel nonclassical transrepression pathway, a direct interaction between ER1 and FXR and as a consequence is a common risk factor for ICP and gallstone disease. Two specific aims are proposed to test the hypothesis. Specific Aim 1 is to determine the mechanisms for estrogen-mediated repression of BSEP expression by the following three approaches: (1) the physical interaction between ER1 and FXR will be firmly established in vitro and in vivo; (2) altered recruitment of FXR and ER1 coregulators to the BSEP promoter by estrogen will be determined; and (3) the region in ER1 directly interacting with FXR will be mapped. Specific Aim 2 is to investigate estrogen-mediated BSEP repression, hepatic and biliary pathological consequences in vivo with the following two approaches: (1) the dynamics of human BSEP transactivation in vivo in mice during the entire pregnancy will be determined with the Living Imaging technology; and (2) the etiological role of estrogen-mediated BSEP repression in estrogen-induced cholestasis and gallstone disease will be investigated in wt and ER1(-/-) mice. Upon completion of the proposed study, we will have firmly established a novel nonclassical estrogen transrepression pathway through a direct interaction between ER1 and FXR, revealed mechanistic insights into such crosstalk between the estrogen/ER1 and bile acids/FXR signaling pathway, and established a common etiological role of BSEP repression in estrogen-induced cholestasis and gallstone disease. The findings will open a new field to advance our understanding on the diverse biological and pathological activities associated with estrogens through investigating estrogen's effects on various FXR target genes. Equally significant, the findings will advance our understanding on the mechanisms and pathogenesis of estrogen-induced ICP and gallstone disease. For the first time, the results will establish a common etiological link between the two distinct but related diseases, and finally, the findings will provide a molecular basis for developing therapeutic agents to treat or prevent those disorders by modulating BSEP expression and ER1/FXR signaling pathways.

描述（由申请人提供）：雌激素除了在正常的性和生殖功能的发展和维持中发挥着众所周知的作用外，在非经典内分泌器官系统，如心血管系统和肝脏中发挥着广泛的生物学作用。胆汁酸是胆固醇的代谢产物，是核受体法内酯X受体（FXR）的一类信号分子。胆汁酸激活FXR可调节无数FXR靶基因，这些基因参与维持胆汁酸、胆固醇、脂质和葡萄糖的稳态。胆汁酸盐输出泵（BSEP）通过激活FXR受胆汁酸正调控，作为胆汁酸小管外排物，在维持肝脏和胆汁中胆汁酸稳态中起关键作用。在胆汁酸水平失衡引起的疾病中，妊娠肝内胆汁淤积症（ICP）和胆结石疾病都与性激素雌激素有关。虽然多种危险因素与这些疾病有关，但研究表明，雌激素在诱发这些疾病中起着关键作用。雌激素诱导的胆汁淤积症和胆结石病均已在动物模型中重现。然而，我们对潜在机制的理解还远远不够。在我们的初步研究中，我们发现雌激素在体外和体内抑制人BSEP的表达，并且这种抑制是由雌激素受体1 （estrogen receptor 1, ER1）通过与FXR的物理相互作用介导的，表明雌激素/ER1与胆汁酸/FXR信号通路之间存在串扰。待验证的中心假设是雌激素下调BSEP表达是通过一种新的非经典转抑制途径介导的，这是ER1和FXR之间的直接相互作用，因此是ICP和胆结石疾病的常见危险因素。为了验证这一假设，提出了两个具体目标。具体目的1是通过以下三种途径确定雌激素介导的BSEP表达抑制机制：(1)ER1和FXR之间的物理相互作用将在体外和体内得到牢固的建立；(2)雌激素改变FXR和ER1共调节因子对BSEP启动子的募集；(3)绘制ER1中与FXR直接相互作用的区域。具体目的2是通过以下两种方法研究雌激素介导的BSEP抑制及其在体内肝脏和胆道的病理后果：(1)利用活体成像技术测定小鼠整个妊娠期体内人BSEP转激活的动态；(2)将在wt和ER1（-/-）小鼠中研究雌激素介导的BSEP抑制在雌激素诱导的胆汁淤积和胆结石疾病中的病因学作用。本研究完成后，我们将通过ER1和FXR的直接相互作用，建立一种新的非经典雌激素转抑制途径，揭示雌激素/ER1和胆汁酸/FXR信号通路之间的串扰机制，并确定BSEP抑制在雌激素诱导的胆汁淤积和胆结石疾病中的共同病因学作用。通过研究雌激素对FXR靶基因的影响，为进一步认识雌激素的多种生物学和病理活性开辟了新的领域。同样重要的是，这些发现将促进我们对雌激素诱导的ICP和胆结石疾病的机制和发病机制的理解。该结果将首次建立两种不同但相关的疾病之间的共同病因学联系，最后，该发现将为开发通过调节BSEP表达和ER1/FXR信号通路来治疗或预防这些疾病的治疗药物提供分子基础。