Retinol-Binding Protein 4 and Its Membrane Receptor STRA6 Control Adipogenesis by Regulating Cellular Retinoid Homeostasis and Retinoic Acid Receptor α Activity
Retinol-Binding Protein 4 and Its Membrane Receptor STRA6 Control Adipogenesis by Regulating Cellular Retinoid Homeostasis and Retinoic Acid Receptor α Activity
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DOI：
10.1128/mcb.00221-13
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发表时间：
2013-10-01
影响因子：
5.3
通讯作者：
Schupp, Michael
中科院分区：
文献类型：
--
作者：
Muenzner, Matthias;Tuvia, Neta;Schupp, Michael
类维生素A是维生素A（视黄醇）衍生物，通过激活特定的核受体（包括视黄酸受体（RAR）和类维生素A X受体（RXR））来调节脂肪生成。循环视黄醇结合蛋白4（RBP 4）及其膜受体STRA 6协调细胞的视黄醇摄取。目前尚不清楚脂肪细胞前体中的视黄醇水平和RAR和RXR的活性是否通过RBP 4/STRA 6联系起来。在这里，我们表明，STRA 6在前体细胞中表达，并由载脂蛋白和全RBP 4亚型决定，介导双向视黄醇转运，控制RAR α活性和随后的脂肪细胞分化。通过诱导RBP 4从肝脏分泌来动员小鼠中的类维生素A储存，激活了含有脂肪组织的基质-血管部分的前体细胞中的RAR α信号传导。加载视黄醇的holo-RBP 4通过激活RAR α阻断培养前体的脂肪细胞分化。值得注意的是，无视黄醇的apo-RBP 4触发了视黄醇流出，减少了细胞类维生素A、RAR α活性和靶基因表达，并与异位STRA 6协同增强了脂肪形成。因此，脂肪细胞前体细胞中的STRA 6将核RAR α活性与循环RBP 4亚型联系起来，其在肥胖小鼠中的比例转向限制其前体的成脂潜力。这种新的串扰确定了RBP 4的视黄醇依赖性代谢功能，这可能对肥胖症的治疗具有重要意义。
Retinoids are vitamin A (retinol) derivatives and complex regulators of adipogenesis by activating specific nuclear receptors, including the retinoic acid receptor (RAR) and retinoid X receptor (RXR). Circulating retinol-binding protein 4 (RBP4) and its membrane receptor STRA6 coordinate cellular retinol uptake. It is unknown whether retinol levels and the activity of RAR and RXR in adipocyte precursors are linked via RBP4/STRA6. Here, we show that STRA6 is expressed in precursor cells and, dictated by the apo-and holo-RBP4 isoforms, mediates bidirectional retinol transport that controls RAR alpha activity and subsequent adipocyte differentiation. Mobilization of retinoid stores in mice by inducing RBP4 secretion from the liver activated RAR alpha signaling in the precursor cell containing the stromal-vascular fraction of adipose tissue. Retinol-loaded holo-RBP4 blocked adipocyte differentiation of cultured precursors by activating RAR alpha. Remarkably, retinol-free apo-RBP4 triggered retinol efflux that reduced cellular retinoids, RAR alpha activity, and target gene expression and enhanced adipogenesis synergistically with ectopic STRA6. Thus, STRA6 in adipocyte precursor cells links nuclear RAR alpha activity to the circulating RBP4 isoforms, whose ratio in obese mice was shifted toward limiting the adipogenic potential of their precursors. This novel cross talk identifies a retinoldependent metabolic function of RBP4 that may have important implications for the treatment of obesity.