R01: FXR and the Gut Microbiome as Modulators of Non-Alcoholic Fatty Liver Disease

R01：FXR 和肠道微生物组作为非酒精性脂肪肝的调节剂

基本信息

批准号：
10022323
负责人：
Andrew Patterson
金额：
$ 36.87万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-23 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10022323
关键词：
16S ribosomal RNA sequencing ADME Study Address Animals Antioxidants Bile Acid Biosynthesis Pathway Bile Acids Biochemical Pathway Biological Availability Biology Ceramides Chemical Engineering Chemicals Communities Data Development Diet Disease model Enterohepatic Circulation Enzymes Excretory function Genetic Genetic Models Glucose Glycine Goals Human In Vitro Institutes Intestines Knock-out Knowledge Laboratories Lactobacillus Lead Link Lipids Liver Malignant Neoplasms Mediating Metabolic Metabolic Diseases Metabolism Metagenomics Mixed Function Oxygenases Modeling Modification Obesity Organic Synthesis Pathogenesis Pharmaceutical Preparations Pharmacodynamics Prevention Property Receptor Signaling Reporting Research Scientist Signal Pathway Signal Transduction Small Intestines Specificity Techniques Tissues Toxic effect Universities Weight Gain absorption bile salts chronic liver disease design genome-wide gut microbiome gut microbiota host microbiota in vivo innovation interest metabolomics metatranscriptomics mid-career faculty mouse model muricholic acid non-alcoholic fatty liver disease nonalcoholic steatohepatitis novel novel strategies novel therapeutics prevent professor programs receptor reconstruction sensor tempol therapeutic target

项目摘要

ABSTRACT Non-alcoholic fatty liver disease (NAFLD) is emerging as one of the most prevalent chronic liver diseases in the world, with non-alcoholic steatohepatitis (NASH) being an extreme form of NAFLD. Our team proposes to investigate the novel concept that intestine-selective FXR antagonism has the potential to prevent or reverse NAFLD/NASH. FXR is the major bile acid sensor in the body and serves to mediate the dialog between the liver and small intestine regarding bile acid levels, bile acid synthesis, transport, and enterohepatic circulation, and also regulates lipid and glucose levels in the liver. As such, FXR was identified in human trials as a promising target for the prevention and/or amelioration of many metabolic diseases, including NAFLD/NASH. We have recently established intestinal FXR as a major regulator of diet-induced obesity and NAFLD, particularly through antagonism of the receptor with the conjugated bile acid tauro-β-muricholic acid (TβMCA). We reported that tempol, a potent antioxidant, inhibited the FXR signaling pathway, due to accumulation of intestinal TβMCA, an antagonist of FXR, resulting from reduced activity of the Lactobacillus-associated bile salt hydroxylase enzyme. We further developed glycine-β-muricholic acid (GlyβMCA), a potent, intestine-selective FXR antagonist that similarly prevents or reversed NAFLD in diet-induced NAFLD models or genetic models, suggesting intestinal FXR as a promising therapeutic target for NAFLD. These observations have led to the novel central hypothesis: Antagonism of intestinal FXR prevents the development of NAFLD In this proposal we plan to address two fundamental gaps in knowledge with respect to FXR antagonism and NAFLD. First, we will identify using a combination of in vitro and in vivo approaches what chemical features define an FXR antagonist and develop a better understanding for how these modifications influence the absorption, distribution, metabolism, and excretion (ADME) of the antagonist and its pharmacodynamic properties. Second, through the innovative use of cutting-edge techniques—including 16S rRNA gene sequencing, metagenomics, metatranscriptomics, and metabolomics—and unique mouse models, we plan to identify how FXR signaling and the gut microbiota are linked in NAFLD pathogenesis. This combination of approaches will allow us to identify new therapeutic FXR antagonists and to accurately assess how these compounds influence downstream FXR signaling pathways with the ultimate goal of developing new NAFLD therapies.

抽象的非酒精性脂肪肝疾病（NAFLD）正在成为最普遍的慢性肝病之一世界，非酒精性脂肪性肝炎（NASH）是NAFLD的极端形式。我们的团队提议研究肠道选择性FXR拮抗作用的新颖概念有可能预防或反向 nafld/nash。 FXR是体内的主要胆汁酸传感器，用于介导肝之间的对话以及有关胆汁酸水平，胆汁酸合成，运输和肠肝循环的小肠，以及还调节肝脏中的脂质和葡萄糖水平。因此，在人类试验中将FXR确定为有希望的预防和/或改善许多代谢疾病的靶标，包括NAFLD/NASH。我们有最近建立了肠道FXR作为饮食诱导的肥胖和NAFLD的主要调节剂，特别是通过接收器与共轭胆汁牛牛tau-β-毛利酸（TβMCA）的拮抗剂。我们报告了这一点模板是一种潜在的抗氧化剂，由于肠道TβMCA的积累而抑制了FXR信号通路 FXR的拮抗剂，是由于乳酸杆菌相关的胆汁盐羟化酶的活性降低而产生的。我们进一步开发了甘氨酸-β-毛利酸（GlyβMCA），这是一种潜力的，肠道选择性的FXR拮抗剂，它是该拮抗剂类似地阻止或反向饮食诱导的NAFLD模型或遗传模型中的NAFLD，这表明肠道 FXR是NAFLD的有前途的治疗靶标。这些观察结果导致了新的中心假设：肠道FXR的对抗阻止了NAFLD的发展在此提案中，我们计划解决有关FXR对抗的知识的两个基本差距和 nafld。首先，我们将使用体外和体内的组合来识别哪些化学特征定义FXR拮抗剂，并更好地了解这些修饰如何影响拮抗剂的抽象，分布，代谢和排泄（ADME）及其药效学特性。其次，通过创新的尖端技术（包括16S rRNA基因）测序，宏基因组学，元文字组学和代谢组学 - 独特的鼠标模型，我们计划确定在NAFLD发病机理中如何连接FXR信号传导和肠道菌群。这种组合方法将使我们能够识别新的治疗性FXR拮抗剂，并准确评估这些拮抗剂化合物影响下游FXR信号通路，其最终目标是开发新的NAFLD 疗法。