Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, MO 63110, USA.
Sci Signal. 2017 Oct 31;10(503):eaan1011. doi: 10.1126/scisignal.aan1011.
The retinoid X receptor α (RXRA) has been implicated in diverse hematological processes. To identify natural ligands of RXRA that are present in hematopoietic cells, we adapted an upstream activation sequence-green fluorescent protein (UAS-GFP) reporter mouse to detect natural RXRA ligands in vivo. We observed reporter activity in diverse types of hematopoietic cells in vivo. Reporter activity increased during granulocyte colony-stimulating factor (G-CSF)-induced granulopoiesis and after phenylhydrazine (PHZ)-induced anemia, suggesting the presence of dynamically regulated natural RXRA ligands in hematopoietic cells. Mouse plasma activated Gal4-UAS reporter cells in vitro, and plasma from mice treated with G-CSF or PHZ recapitulated the patterns of reporter activation that we observed in vivo. Plasma from mice with dietary vitamin A deficiency only mildly reduced RXRA reporter activity, whereas plasma from mice on a fatty acid restriction diet reduced reporter activity, implicating fatty acids as plasma RXRA ligands. Through differential extraction coupled with mass spectrometry, we identified the long-chain fatty acid C24:5 as a natural RXRA ligand that was greatly increased in abundance in response to hematopoietic stress. Together, these data suggest that natural RXRA ligands are present and dynamically increased in abundance in mouse hematopoietic cells in vivo.
视黄酸受体 X 受体α（RXRA）参与了多种血液学过程。为了鉴定存在于造血细胞中的 RXRA 的天然配体，我们采用了上游激活序列-绿色荧光蛋白（UAS-GFP）报告基因小鼠，以在体内检测天然 RXRA 配体。我们观察到报告基因在体内多种类型的造血细胞中具有活性。在粒细胞集落刺激因子（G-CSF）诱导的粒细胞生成和苯肼（PHZ）诱导的贫血后，报告基因活性增加，这表明造血细胞中存在动态调节的天然 RXRA 配体。小鼠血浆在体外激活 Gal4-UAS 报告基因细胞，G-CSF 或 PHZ 处理的小鼠血浆再现了我们在体内观察到的报告基因激活模式。饮食中缺乏维生素 A 的小鼠血浆仅轻微降低 RXRA 报告基因活性，而脂肪酸限制饮食的小鼠血浆降低报告基因活性，表明脂肪酸是血浆 RXRA 配体。通过差异提取结合质谱分析，我们鉴定出长链脂肪酸 C24:5 是一种天然的 RXRA 配体，它在造血应激时丰度大大增加。综上所述，这些数据表明，天然的 RXRA 配体存在于并在体内小鼠造血细胞中动态增加。
