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

Farnesoid X 受体在 NASH 发展中的组织特异性功能

• 批准号: 10750016
• 负责人: Zakiyah Henry
• 金额: $ 4.26万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10750016
• 关键词: Acute-Phase Proteins; Age; Agonist; Albumins; Apoptotic; Bile Acid Biosynthesis Pathway; Bile Acids; Biochemistry; Biological Markers; Biological Process; Biomedical Research; Cell Death; Cells; Cellular Membrane; Ceramides; Characteristics; Cholesterol; Cholesterol Homeostasis; Chronic; Data; Detergents; Development; Diet; Enterocytes; FDA approved; Fatty Liver; Fatty acid glycerol esters; Fellowship; Female; Fibrosis; G-Protein-Coupled Receptors; GPBAR1 gene; Gene Expression; Genotype; Goals; Health; Hepatic; Hepatocyte; Histologic; Homeostasis; Human; Immunohistochemistry; Individual; Inflammation; Inflammatory; Intervention; Intestines; Knock-out; Knockout Mice; Life Style; Ligands; Lipids; Liver; LoxP-flanked allele; Mediating; Metabolic Diseases; Mission; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Organ; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Population; Prevention; Principal Investigator; Production; Property; Pruritus; Quality of life; Receptor Activation; Research; Role; Scientist; Serum; Side; Small Intestines; Specificity; Testing; Therapeutic; Tissue-Specific Gene Expression; Tissues; Training; United States; Up-Regulation; Ursodeoxycholic Acid; Vision; Western Blotting; Work; antagonist; blood glucose regulation; cell type; chronic liver disease; combat; cytotoxic; dietary control; efficacious treatment; endoplasmic reticulum stress; fast food; fatty acid oxidation; glucagon-like peptide 1; improved; lipid biosynthesis; liver inflammation; liver injury; liver transplantation; male; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel therapeutics; pharmacologic; prevent; protective effect; protein expression; receptor; receptor expression; side effect; simple steatosis; sugar; targeted treatment; transcription factor; transcriptome sequencing; villin

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.

项目摘要/摘要 非酒精性脂肪性肝病(NAFLD)是一种以脂肪堆积为特征的一系列疾病 肝脏被称为脂肪变性。大约25%的美国人患有非酒精性脂肪肝，其中大约30%的人患有非酒精性脂肪肝 人们患有非酒精性脂肪性肝炎(NASH)。NASH是更严重和更渐进的形式 以肝脏脂肪变性、肝细胞膨胀、炎症和纤维化为特征的非酒精性脂肪性脂肪肝。纳什也是 这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- 批准用于NASH的治疗；然而，一个新兴的靶点是法尼类X受体(FXR)。FXR是一种 配体激活的转录因子在肝脏和肠道等多种组织中高表达，并在 胆汁酸(BA)动态平衡的主要调节剂。BA被牵连到NASH开发和 雄性小鼠的进展和FXR缺乏会导致更严重的NASH发展。因为FXR 负向调节BA的产生，已开发出全身FXR激动剂的合成配体 来治疗纳什。这些全身调节剂虽然有益，但也会产生不利的副作用，如 胆固醇稳态失衡，从而解释了FXR组织特异性激活在 开发治疗NASH的新疗法，以消除任何潜在的有害后果。我们的预赛 数据表明，在小鼠肝脏中表达的FXR的缺失在NASH的发生中更关键 与在小肠表达的FXR的缺失相比。导致这些问题的根本机制 不同之处没有得到很好的阐明。了解这些机制有助于FXR在 特定于组织和特定细胞的方式将使科学家能够开发安全、有针对性和有效的治疗方法 为了纳什。除了确定哪种器官或细胞类型最适合作为合成目标之外 NASH的药物干预，决定FXR激活或失活对 NASH的治疗需要确定，特别是关于肠道内的FXR。相互矛盾的研究表明 肠道FXR激动剂和拮抗剂均有利于NASH的治疗。目标一号将决定 法尼醇X受体在小鼠NASH发生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的预防作用。通过完成 在本F31奖学金中描述的研究和培训，首席调查员将接受基础 促进代谢性疾病发展和预防的生物医学研究和生物过程； 聚焦在纳什身上。首席调查员将准备进行独立研究并加强 科学工作者的多样性，并协助改善个人的健康和生活质量 患有这种慢性肝病，这符合美国国立卫生研究院的使命和愿景 糖尿病与消化和肾脏疾病。