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

• 批准号: 10228735
• 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
• 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/10228735
• 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; 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; diet-induced obesity; 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

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.

摘要 非酒精性脂肪性肝病(NAFLD)是世界上最常见的慢性肝病之一。 非酒精性脂肪性肝炎(NASH)是NAFLD的一种极端形式。我们团队建议 探索肠道选择性FXR拮抗剂有可能预防或逆转的新概念 NAFLD/NASH。FXR是体内主要的胆汁酸感受器，起着调节肝脏和肝脏之间的对话的作用 和小肠的胆汁酸水平、胆汁酸合成、转运和肠肝循环。 还调节肝脏中的脂肪和葡萄糖水平。因此，FXR在人体试验中被确定为有希望的 预防和/或改善包括NAFLD/NASH在内的许多代谢性疾病的目标。我们有 最近建立了肠道FXR作为饮食诱导的肥胖和NAFLD的主要调节因素，特别是通过 受体与结合胆汁酸牛磺酸-β-鼠李酸(T-β)的拮抗作用。我们报道了 一种有效的抗氧化剂坦普尔，由于在肠道中T-β-MCA的积聚，抑制了FXR信号通路。 FXR的拮抗剂，由于乳杆菌相关的胆盐羟基酶活性降低而引起。 我们进一步开发了甘氨酸-β-鼠李酸(GlyβMCA)，一种有效的肠道选择性FXR拮抗剂， 在饮食诱导的NAFLD模型或遗传模型中，类似地预防或逆转NAFLD，提示肠道 FXR作为NAFLD有希望的治疗靶点。这些观察结果导致了新的中心假说： 肠道FXR的拮抗作用阻止NAFLD的发展 在这项提案中，我们计划解决关于FXR拮抗和 NAFLD。首先，我们将使用体外和体内相结合的方法来确定哪些化学特征 定义FXR拮抗剂，并更好地了解这些修改如何影响 拮抗剂的吸收、分布、代谢和排泄及其药效学 属性。第二，通过创新使用尖端技术--包括16S rRNA基因 测序、元基因组学、元转录组学和代谢组学--以及独特的小鼠模型，我们计划 明确FXR信号和肠道微生物区系在NAFLD发病机制中的联系。这一组合 这些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 化合物影响下游FXR信号通路，最终目标是开发新的NAFLD 治疗。