Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pharmacology, Berlin, Germany.
Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria.
J Lipid Res. 2022 Oct;63(10):100268. doi: 10.1016/j.jlr.2022.100268. Epub 2022 Aug 27.
Hepatocytes secrete retinol-binding protein 4 (RBP4) into circulation, thereby mobilizing vitamin A from the liver to provide retinol for extrahepatic tissues. Obesity and insulin resistance are associated with elevated RBP4 levels in the blood. However, in a previous study, we observed that chronically increased RBP4 by forced Rbp4 expression in the liver does not impair glucose homeostasis in mice. Here, we investigated the effects of an acute mobilization of hepatic vitamin A stores by hepatic overexpression of RBP4 in mice. We show that hepatic retinol mobilization decreases body fat content and enhances fat turnover. Mechanistically, we found that acute retinol mobilization increases hepatic expression and serum levels of fibroblast growth factor 21 (FGF21), which is regulated by retinol mobilization and retinoic acid in primary hepatocytes. Moreover, we provide evidence that the insulin-sensitizing effect of FGF21 is associated with organ-specific adaptations in retinoid homeostasis. Taken together, our findings identify a novel crosstalk between retinoid homeostasis and FGF21 in mice with acute RBP4-mediated retinol mobilization from the liver.
肝细胞将视黄醇结合蛋白 4（RBP4）分泌到血液循环中，从而将肝脏中的维生素 A 动员出来，为肝外组织提供视黄醇。肥胖症和胰岛素抵抗与血液中 RBP4 水平升高有关。然而，在之前的一项研究中，我们观察到肝脏中 RBP4 的强制表达导致 RBP4 水平持续升高，并不会损害小鼠的葡萄糖稳态。在这里，我们研究了通过肝内 RBP4 的过表达来急性动员肝内维生素 A 储存对小鼠的影响。我们发现肝内视黄醇动员会降低体脂肪含量并增强脂肪周转。从机制上讲，我们发现急性视黄醇动员会增加肝细胞中纤维母细胞生长因子 21（FGF21）的表达和血清水平，而 FGF21 受视黄醇动员和视黄酸调节。此外，我们提供了证据表明，FGF21 的胰岛素增敏作用与急性 RBP4 介导的肝内视黄醇动员引起的视黄醇稳态的器官特异性适应有关。总之，我们的研究结果确定了在急性 RBP4 介导的肝内视黄醇动员的小鼠中，视黄醇稳态和 FGF21 之间存在一种新的串扰。
