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Regulation of retinoid homeostasis by the hormone FGF21

激素 FGF21 对类维生素A稳态的调节

基本信息

批准号：
390217139
负责人：
Professor Dr. Michael Schupp, Ph.D.
金额：
--
依托单位：
Institut für Molekulare Biowissenschaften
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2017
资助国家：
德国
起止时间：
2016-12-31 至 2022-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/390217139?language=en
关键词：
Regulation retinoid homeostasis hormone FGF21

项目摘要

Retinoids (Vitamin A (retinol) and its derivatives) are essential micronutrients and involved in a number of physiological processes by acting as ligands for nuclear receptors or as photon-acceptor in vision. More than 70% of all retinoids in the body are stored as retinyl esters in specialized liver cells. These stores are mobilized, involving the hydrolysis of retinyl esters and the secretion of the retinol binding protein 4 (RBP4):retinol complexes by hepatocytes. Especially during fasting, when the supply of lipoprotein-transported retinoids is negligible, circulating RBP4 is the principal source of retinol to meet cellular demands. The molecular signals that coordinate retinoid homeostasis between liver and extra-hepatic tissues are unknown. We made the surprising observation that fasting of mice reduced the amount of retinyl esters in white adipose tissue (WAT) but not liver. This suggests that retinol mobilization from the liver is replenished by reverse retinol transport from extrahepatic tissues back to the liver. Strikingly, when depleted of their hepatic retinyl ester stores, mice exhibited increased expression and secretion of the fasting-hormone fibroblast growth factor 21 (FGF21) from the liver. This was associated with increased lipolysis in WAT as well as hepatic ketogenesis, and led to improved glucose tolerance, suggesting a novel function of FGF21 in retinoid homeostasis and interorgan crosstalk. Thus, we hypothesize that FGF21 induces repartitioning of retinoids from WAT to the liver by activating retinyl ester hydrolases such as hormone-sensitive lipase. We propose that this pathway is relevant during physiological conditions (e.g. adaptation to feeding/fasting) and disturbed in metabolic diseases such as obesity and insulin resistance. In this project we propose to determine (i) the molecular events of fasting-induced retinol mobilization from adipose tissue and the requirement of FGF21, (ii) the molecular link between hepatic retinoid content and FGF21 expression, (iii) the role of FGF21-mediated interorgan crosstalk in metabolically-challenged mice (e.g. diet-induced obesity), and (iv) whether this interorgan crosstalk, involving reverse retinol transport to the liver, is required for the beneficial effects of FGF21 on insulin sensitivity. Addressing these aims will elucidate the relevance of the RBP4/FGF21/retinoid axis for novel therapeutic interventions that could target metabolic diseases.

类维生素A（维生素A（视黄醇）及其衍生物）是人体必需的微量营养素，通过作为核受体的配体或视觉中的光子受体参与许多生理过程。体内超过70%的类维生素A以视黄酯的形式储存在专门的肝细胞中。这些储存被动员，涉及视黄酯的水解和视黄醇结合蛋白4（RBP 4）的分泌：肝细胞的视黄醇复合物。特别是在禁食期间，当脂蛋白转运的类维生素A的供应可以忽略不计时，循环RBP 4是满足细胞需求的视黄醇的主要来源。在肝脏和肝外组织之间协调维甲酸稳态的分子信号是未知的。我们发现了令人惊讶的观察结果，即小鼠禁食减少了白色脂肪组织（WAT）中视黄酯的含量，但没有减少肝脏中的视黄酯的含量。这表明从肝脏动员的视黄醇通过从肝外组织反向转运回到肝脏来补充。引人注目的是，当耗尽它们的肝脏视黄酯储存时，小鼠表现出从肝脏增加的禁食激素成纤维细胞生长因子21（FGF 21）的表达和分泌。这与WAT中脂肪分解增加以及肝酮生成相关，并导致葡萄糖耐量改善，表明FGF 21在类维生素A稳态和器官间串扰中的新功能。因此，我们假设FGF 21通过激活视黄酯水解酶如对葡萄糖敏感的脂肪酶诱导类维生素A从WAT重新分配到肝脏。我们认为，这一途径在生理条件下（例如，适应进食/禁食）是相关的，并在代谢疾病如肥胖和胰岛素抵抗中受到干扰。在这个项目中，我们建议确定（i）禁食诱导的脂肪组织中视黄醇动员的分子事件和FGF 21的需求，（ii）肝脏类维生素A含量和FGF 21表达之间的分子联系，（iii）代谢挑战小鼠中FGF 21介导的器官间串扰的作用（例如饮食诱导的肥胖症），和（iv）这种器官间串扰（涉及向肝脏的反向视黄醇转运）是否是FGF 21对胰岛素敏感性的有益作用所需的。解决这些目标将阐明RBP 4/FGF 21/类维生素A轴的相关性，用于靶向代谢性疾病的新型治疗干预。