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Retinoic acid receptor, lipid metabolism, and fatty liver disease

视黄酸受体、脂质代谢和脂肪肝疾病

基本信息

批准号：
8817210
负责人：
MENGWEI ZANG
金额：
$ 39.15万
依托单位：
BOSTON MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-01-01 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8817210
关键词：
Address Adenoviruses Adverse effects Affect Agonist American Area Attenuated Automobile Driving Body Weight Cirrhosis Clinical Data Development Diabetes Mellitus Diet Disease Fasting Fatty Liver Fatty acid glycerol esters Gene Delivery Gene Expression Gene Expression Profiling Gene Transfer Genetic Transcription Glucose Half-Life Health Hepatic Hepatocyte Homeostasis Hormones Human Hypoglycemia Immunohistochemistry In Vitro Inflammation Insulin Insulin Resistance Intervention Knockout Mice Knowledge Ligands Lipids Liver Liver diseases Mediating Metabolic Metabolic Diseases Metabolic Pathway Metabolic stress Microarray Analysis Mission Mitochondria Molecular Molecular Biology Monkeys Mus Mutagenesis National Institute of Diabetes and Digestive and Kidney Diseases Non-Insulin-Dependent Diabetes Mellitus Nuclear Nuclear Receptors Nuclear Translocation Nutrient Nutritional Obese Mice Obesity Pathway interactions Physiological Physiology Play Primary carcinoma of the liver cells Production Proteolytic Processing Public Health Receptor Activation Regulation Research Retinoic Acid Receptor Role SRE-1 binding protein Series Signal Transduction Staging Starvation Stress Sucrose Testing Therapeutic Therapeutic Agents Tretinoin United States Vitamin A base blood glucose regulation cancer therapy chromatin immunoprecipitation chronic liver disease combat deprivation detection of nutrient effective therapy fatty acid oxidation feeding fibroblast growth factor 21 improved in vivo innovation ketogenesis lipid biosynthesis lipid metabolism metabolomics mimetics new therapeutic target non-alcoholic fatty liver novel novel therapeutics overexpression preclinical study promoter public health relevance receptor function research study response therapeutic target transcription factor

项目摘要

DESCRIPTION (provided by applicant): The overall objective of this proposal is to define the metabolic consequences, interventions, and mechanisms of a novel signaling cascade involving retinoic acid receptor (RAR) and fibroblast growth factor 21 (FGF21) in non-alcoholic fatty liver disease (NAFLD), one of the most common chronic liver diseases in the United States. Hepatic steatosis is an early and reversible stage of NAFLD, which can advance to irreversible cirrhosis and hepatocellular carcinoma with no effective therapies. Therefore, the discovery of novel metabolic pathways that present therapeutic targets is required to effectively manage NAFLD. As the major metabolite of vitamin A, all-trans-retinoic acid (RA) is a natural ligand of retinoic acid receptor (RAR) and is clinically used for anti-cancer therapy. However, the role of different RAR isotypes in regulating liver physiology and NAFLD is a novel and unexplored area. While the newly discovered hepatocyte-derived hormone FGF21 is emerging as a potential therapeutic target for treating metabolic disease, the upstream regulators of FGF21 remain largely unknown. Our recent discovery of a previously unrecognized crosstalk between RAR and FGF21 has changed this view and leads to a series of novel and exciting data that represent the core of our specific aims. Specifically, our results show that 1) FGF21 gene expression is induced by RAR�r RAR�ut not by RAR?; 2) RA increases fatty acid oxidation at least partially through FGF21 in vitro; 3) Hepatic overexpression of RAR�y an adenoviral gene delivery improves hepatic steatosis and insulin resistance in diet-induced obese mice; and 4) Hepatic overexpression of RAR�lso results in increased FGF21 production in mice. To extend these exciting observations, the Central Hypothesis is that hepatic RAR functions as a transcriptional regulator of FGF21 to maintain hepatic lipid homeostasis during prolonged fasting and to attenuate the progression of NAFLD. There are three Specific Aims. 1) To determine whether hepatic RAR regulates FGF21 induction and lipid homeostasis under nutrient deprivation conditions. State-of-the-art approaches including gene expression profiling analysis, metabolomics and lipidomics analyses will be conducted to identify new regulators and lipid metabolites involving RAR and/or FGF21 signaling. 2) To determine whether hepatic RAR slows the development of NAFLD and insulin resistance through FGF21 using in vivo adenoviral gene transfer targeting each RAR isotype and FGF21-/- mice. 3) To elucidate the molecular basis of the integrated signaling of hepatic RAR and FGF21 in de novo lipogenesis under in vivo and in vitro conditions of metabolic stress. Overall, accomplishing this proposal will establish th physiological role of an RAR-FGF21 signaling in the regulation of lipid homeostasis. These innovative experiments are expected to identify new therapeutic targets for the management of NAFLD and its related metabolic disease.

描述（由申请人提供）：本提案的总体目标是确定涉及维甲酸受体（RAR）和成纤维细胞生长因子21 （FGF21）的新型信号级联在非酒精性脂肪性肝病（NAFLD）中的代谢后果、干预和机制，NAFLD是美国最常见的慢性肝病之一。肝脂肪变性是NAFLD的早期可逆阶段，可发展为不可逆的肝硬化和肝细胞癌，目前尚无有效的治疗方法。因此，需要发现新的代谢途径，提供治疗靶点，以有效地管理NAFLD。全反式维甲酸（all-trans-retinoic acid， RA）是维生素A的主要代谢物，是维甲酸受体（retinoic acid receptor， RAR）的天然配体，临床上用于抗癌治疗。然而，不同的RAR同型在调节肝脏生理和NAFLD中的作用是一个新的和未开发的领域。虽然新发现的肝细胞源性激素FGF21正在成为治疗代谢性疾病的潜在治疗靶点，但FGF21的上游调节因子在很大程度上仍然未知。我们最近发现的RAR和FGF21之间先前未被识别的串扰改变了这一观点，并导致了一系列新颖而令人兴奋的数据，这些数据代表了我们特定目标的核心。具体来说，我们的结果表明：1)FGF21基因的表达是由RAR诱导的，而不是由RAR诱导的；2) RA至少部分通过FGF21增加体外脂肪酸氧化；3)肝脏过表达RAR - y和腺病毒基因传递可改善饮食诱导的肥胖小鼠肝脏脂肪变性和胰岛素抵抗；4)肝脏过表达RAR也导致小鼠FGF21的产生增加。为了扩展这些令人兴奋的观察结果，中心假设是肝脏RAR作为FGF21的转录调节因子，在长时间禁食期间维持肝脏脂质稳态，并减缓NAFLD的进展。具体目的有三个：1)确定营养剥夺条件下肝脏RAR是否调节FGF21诱导和脂质稳态。将采用最先进的方法，包括基因表达谱分析、代谢组学和脂质组学分析，以确定涉及RAR和/或FGF21信号的新的调节因子和脂质代谢物。2)采用针对各RAR同型和FGF21-/-小鼠的体内腺病毒基因转移，确定肝脏RAR是否通过FGF21延缓NAFLD和胰岛素抵抗的发展。3)阐明体内和体外代谢应激条件下肝脏RAR和FGF21综合信号在新生脂肪生成中的分子基础。总之，完成这一提议将确定RAR-FGF21信号在调节脂质稳态中的生理作用。这些创新实验有望为NAFLD及其相关代谢疾病的治疗确定新的治疗靶点。