Retinoic acid receptor, lipid metabolism, and fatty liver disease

描述(申请人提供)：这项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)的新的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。肝脏脂肪变性是NAFLD的早期和可逆性阶段，在缺乏有效治疗的情况下可进展为不可逆转的肝硬变和肝细胞癌。因此，需要发现新的代谢途径来提供治疗靶点，以有效地管理非酒精性脂肪肝。全反式维甲酸(RA)是维生素A的主要代谢物，是维甲酸受体(RAR)的天然配体，临床上用于抗癌治疗。然而，不同的RAR亚型在调节肝脏生理和NAFLD中的作用是一个新的和未被探索的领域。虽然新发现的肝细胞衍生激素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不清楚。我们最近发现了RAR和FGF21之间以前未被认识到的串扰，改变了这种观点，并产生了一系列新颖和令人兴奋的数据，代表了我们特定目标的核心。具体地说，我们的结果表明：1)RAR�r RAR�而不是RAR？诱导FGF21基因的表达；2)RA在体外至少部分通过FGF21增加脂肪酸氧化；3)肝脏过度表达RAR�y腺病毒可以改善饮食诱导的肥胖小鼠的肝脏脂肪变性和胰岛素抵抗；以及4)肝脏过度表达RAR�LSO导致小鼠肝脏FGF21产生增加。为了推广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，在长期禁食期间维持肝脏脂类平衡，并延缓NAFLD的进展。有三个具体目标。1)探讨在营养缺乏条件下，肝脏RAR是否调节FGF21的诱导和脂质稳态。将采用最先进的方法，包括基因表达谱分析、代谢组学和脂类组学分析，以确定涉及RAR和/或FGF21信号的新调节剂和脂质代谢物。2)通过体内靶向RAR各亚型和FGF21-/-小鼠的腺病毒基因转移，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、外代谢应激条件下肝组织RAR和FGF21整合信号在新生脂肪形成中的分子基础。总体而言，完成这一提议将确立RAR-FGF21信号在调节脂质稳态中的生理作用。这些创新的实验有望为NAFLD及其相关代谢性疾病的管理确定新的治疗目标。

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.