The Tissue-Specific Functionality of the Farnesoid X Receptor in NASH Development

项目总结/摘要 非酒精性脂肪性肝病（NAFLD）是一系列以肝脏中的脂质积聚为特征的病症。 肝脏脂肪变性大约25%的美国人口患有NAFLD，其中大约30%的人患有NAFLD。 人群患有非酒精性脂肪性肝炎（NASH）。NASH是NASH的更严重和进行性形式， NAFL的特征是肝脏脂肪变性、肝细胞气球样变、炎症和纤维化。NASH也是 美国肝移植的领先指标。除了生活方式的改变，目前没有FDA- 然而，一个新兴的靶标是法尼醇X受体（FXR）。FXR是一个 配体激活的转录因子在许多组织如肝和肠中高度表达， 胆汁酸（BA）体内平衡的主要调节剂。BA与NASH的发展有关， 在雄性小鼠中，NASH进展和FXR缺乏导致更严重的NASH发展。因为FXR 负调节BA的产生，已经开发了作为全身FXR激动剂的合成配体 治疗NASH虽然有益，但这些全身调节剂导致不利的副作用，例如 胆固醇稳态失衡，从而解释了FXR组织特异性激活的重要性， 开发NASH的新疗法以消除任何潜在的有害后果。我们的初步 数据表明，小鼠肝脏中表达的FXR的缺失在NASH的发展中更为关键， 与小肠中表达的FXR的缺失相比。导致这些的潜在机制 没有很好地阐明差异。了解这些有助于FXR功能的机制， 组织特异性和细胞特异性的方式将允许科学家开发安全，有针对性和有效的治疗方法 NASH除了确定哪种器官或细胞类型最适合于靶向合成 药物干预NASH，决定FXR激活或失活是否是最有益的， 需要确定NASH的治疗，特别是关于肠道中的FXR。研究表明， 肠FXR激动和拮抗作用在NASH的治疗中都是有益的。目标1将决定 法尼醇X受体在小鼠NASH发展中的组织特异性作用。目标2将决定 FXR拮抗剂熊去氧胆酸对小鼠NASH预防的作用。通过完成 本F31奖学金中描述的研究和培训，主要研究者将接受基本的培训， 生物医学研究和生物过程有助于代谢疾病的发展和预防， 专注于NASH首席研究员将准备进行独立研究，并提高 科学劳动力的多样性，并协助改善个人的健康和生活质量 患有这种慢性肝病，这符合国家肝病研究所的使命和愿景。 糖尿病、消化系统和肾脏疾病。

PROJECT SUMMARY/ABSTRACT Non-alcoholic fatty liver disease (NAFLD) is a spectrum of conditions characterized by lipid accumulation in the liver known as steatosis. Approximately 25% of the US population have NAFLD and approximately 30% of that population suffer from non-alcoholic steatohepatitis (NASH). NASH is the more severe and progressive form of NAFL that is characterized by liver steatosis, hepatocellular ballooning, inflammation, and fibrosis. NASH is also the leading indicator for liver transplantation in the US. Other than lifestyle changes, there is no current FDA- approved therapeutic for NASH; however, one emerging target is the Farnesoid X Receptor (FXR). FXR is a ligand activated transcription factor highly expressed in numerous tissues such as the liver and intestine and is a major regulator in bile acid (BA) homeostasis. BAs have been implicated in NASH development and progression and FXR deficiency in male mice leads to more severe NASH development. Because FXR negatively regulates BA production, synthetic ligands that are whole-body FXR agonists have been developed to treat NASH. Although beneficial, these whole-body modulators contribute to unfavorable side effects such as cholesterol homeostasis imbalance, thereby explaining the importance of FXR tissue-specific activation in the development of novel therapeutics for NASH to negate any potential harmful consequences. Our preliminary data suggests that deletion of FXR expressed in the livers of mice is more critical in NASH development compared to the deletion of FXR expressed in the small intestine. The underlying mechanisms leading to these differences are not well elucidated. Understanding these mechanisms contributing to FXR functionality in a tissue-specific and cell-specific manner will allow scientists to develop safe, targeted, and efficacious therapies for NASH. In addition to determining which organ or cell type is most appropriate to target for the synthesis of pharmacological interventions for NASH, deciding whether FXR activation or inactivation is most beneficial in the treatment of NASH needs to be determined, particularly pertaining to FXR in the gut. Conflicting studies show that both intestinal FXR agonism and antagonism are beneficial in the treatment of NASH. Aim 1 will determine the tissue-specific role of the the farnesoid X receptor in NASH development in mice. Aim 2 will determine the effects of ursodeoxycholic acid, an FXR antagonist, on NASH prevention in mice. Through the completion of the research and training described in this F31 Fellowship, the Principal Investigator will be trained in basic biomedical research and biological processes contributing to metabolic disease development and prevention, focusing on NASH. The Principal Investigator will be prepared to conduct independent research and enhance the diversity of the scientific workforce, and to assist in improving the health and quality of life of individuals suffering from this chronic liver disease, which is in line with the mission and vision of the National Institute of Diabetes and Digestive and Kidney Diseases.