Regulation of Bile Acid Metabolism and Signaling in Metabolic Diseases

代谢疾病中胆汁酸代谢和信号传导的调节

• 批准号: 10301001
• 负责人: Tiangang Li
• 金额: $ 29.27万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-05 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10301001
• 关键词: Address; Attenuated; Autophagocytosis; Bile Acid Biosynthesis Pathway; Bile Acids; Biochemical Pathway; Biogenesis; CYP7A1 gene; Catabolism; Cause of Death; Cell Nucleus; Cellular biology; Cholesterol; Cholesterol Esters; Cholesterol Homeostasis; Chronic; Complex; Diabetes Mellitus; Dyslipidemias; E-Box Elements; Endocrine; Excision; FGF19 gene; FRAP1 gene; Failure; Family; Fatty acid glycerol esters; Feedback; Functional disorder; Gene Delivery; Genes; Genetic; Genetic Transcription; Goals; Helix-Turn-Helix Motifs; Hepatic; Hepatocyte; Homeostasis; Hormones; Human; Imaging Techniques; Impairment; Inflammation; Inflammatory Response; Intestines; Knock-out; Leucine Zippers; Link; Lipids; Liver; Liver diseases; Lysosomal Storage Diseases; Lysosomes; Mediating; Metabolic; Metabolic Control; Metabolic Diseases; Modeling; Molecular; Molecular Biology; Mus; Neurodegenerative Disorders; Nutrient; Organ; Organelles; Orthologous Gene; Overnutrition; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Phosphorylation; Physiological; Proteomics; Proto-Oncogene Proteins c-akt; Recycling; Regulation; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Starvation; Stress; Techniques; Testing; Therapeutic; Tissues; base; bile acid metabolism; body system; cardiovascular disorder risk; cell type; chronic liver disease; design; gene network; gut-liver axis; hepatocyte injury; high risk; human disease; improved; inhibitor; insight; intrahepatic; liver metabolism; molecular imaging; mouse model; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; response; therapeutically effective; transcription factor; uptake

Project Summary Diabetes and non-alcoholic fatty liver disease (NAFLD) are closely associated with hepatic fat and cholesterol accumulation, hepatocyte organelle dysfunction, low grade inflammation, and dyslipidemia. Patients with diabetes and NAFLD have significantly higher risk of cardiovascular disease, which remains the leading cause of death worldwide. Hepatic bile acid synthesis is the only major cholesterol catabolism mechanism in the body. Furthermore, bile acids act as signaling molecules to critically control metabolic homeostasis and inflammatory response. Different therapeutic approaches targeting the bile acid dynamics and signaling pathways have shown great promise for treating metabolic and chronic liver diseases. However, how modulating the enterohepatic bile acid signaling impacts the complex metabolic network via distinct mechanism of actions is still incompletely understood. New mechanistic insights are clearly needed to establish the molecular basis for developing effective bile acid-based therapies. The goal of this study is to define a new role of Transcriptional Factor EB (TFEB) in the regulation of hepatic bile acid metabolism. TFEB belongs to the basic helix-loop-helix leucine zipper family of transcriptional factors and was recently identified as a nutrient and stress-sensing master regulator of lysosomal biogenesis in various cell types, which has led to a paradigm shift in our understanding of how lysosomal pathways can be dynamically regulated in response to various nutrient and stress signals to maintain cellular homeostasis. Current studies suggest that TFEB may be an attractive target for treating neurodegenerative diseases, lysosomal storage disease, and metabolic diseases. However, the role of TFEB in regulating the complex hepatic metabolism is incompletely understood, and the TFEB regulation of hepatic bile acid metabolism has not been explored. Here we found that TFEB is a strong inducer of bile acid synthesis, and hepatic TFEB itself is inhibited by the intestine bile acid sensing hormone FGF15/19. Identification of this gut-liver signaling crosstalk has led to an interesting new concept of pharmacologically targeting this regulatory loop to enhance hepatic TFEB function and improve metabolic homeostasis. Three specific aims are designed to first establish that liver TFEB is a novel bile acid sensing transcriptional factor and a key effector in the gut-liver bile acid signaling crosstalk regulation of liver metabolism, and further determine the pathophysiological significance and therapeutic implications of this signaling regulatory loop. This study will employ several experimental mouse models through AAV8-mediated hepatocyte-specific gene delivery, tissue-specific genetic knockout, and pharmacological treatment approaches. These models will be investigated with a combination of physiological, molecular biology, and cell biology techniques and unbiased proteomics approaches. By employing these state-of-the-art models and techniques, our working hypothesis can be rigorously tested and new mechanistic insights will be obtained.

项目概要 糖尿病和非酒精性脂肪肝（NAFLD）与肝脏脂肪和胆固醇密切相关 蓄积、肝细胞细胞器功能障碍、低度炎症和血脂异常。患者患有 糖尿病和非酒精性脂肪肝 (NAFLD) 患心血管疾病的风险显着更高，而心血管疾病仍然是主要原因 全世界的死亡。肝胆汁酸合成是胆固醇分解代谢的唯一主要机制。 身体。此外，胆汁酸作为信号分子来严格控制代谢稳态和 炎症反应。针对胆汁酸动力学和信号传导的不同治疗方法 这些途径在治疗代谢性和慢性肝病方面显示出巨大的前景。然而，如何 调节肠肝胆汁酸信号通过不同的方式影响复杂的代谢网络 作用机制仍不完全清楚。显然需要新的机制见解 为开发有效的胆汁酸疗法奠定分子基础。这项研究的目标是 定义了转录因子 EB (TFEB) 在肝胆汁酸代谢调节中的新作用。铁氟龙 属于转录因子的基本螺旋-环-螺旋亮氨酸拉链家族，最近被鉴定 作为各种细胞类型中溶酶体生物发生的营养和压力感应主调节器，这导致 我们对溶酶体途径如何动态调节响应的理解发生了范式转变 各种营养和压力信号以维持细胞稳态。目前的研究表明 TFEB 可能 成为治疗神经退行性疾病、溶酶体贮积病和代谢性疾病的有吸引力的靶标 疾病。然而，TFEB 在调节复杂的肝脏代谢中的作用尚不完全清楚， TFEB对肝脏胆汁酸代谢的调节尚未被探索。在这里我们发现 TFEB 是 胆汁酸合成的强诱导剂，肝脏 TFEB 本身受到肠道胆汁酸感应的抑制 激素 FGF15/19。这种肠道-肝脏信号串扰的识别产生了一个有趣的新概念 药理学上靶向该调节环路以增强肝 TFEB 功能并改善代谢 体内平衡。设计了三个具体目标，首先确定肝脏 TFEB 是一种新型胆汁酸传感技术 转录因子和肠道-肝脏胆汁酸信号串扰调节肝脏的关键效应子 代谢，并进一步确定其病理生理意义和治疗意义 信号调节环路。本研究将通过 AAV8 介导采用几种实验小鼠模型 肝细胞特异性基因传递、组织特异性基因敲除和药物治疗 接近。这些模型将结合生理学、分子生物学和细胞学进行研究 生物学技术和公正的蛋白质组学方法。通过采用这些最先进的模型和 技术，我们的工作假设可以得到严格的测试，并将获得新的机制见解。