Salameh Ahmad, Daquinag Alexes C, Staquicini Daniela I, An Zhiqiang, Hajjar Katherine A, Pasqualini Renata, Arap Wadih, Kolonin Mikhail G
Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA.
University of New Mexico Comprehensive Cancer Center and Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA.
JCI Insight. 2016 Jul 7;1(10). doi: 10.1172/jci.insight.86351.
We have previously identified prohibitin (PHB) and annexin A2 (ANX2) as proteins interacting on the surface of vascular endothelial cells in white adipose tissue (WAT) of humans and mice. Here, we demonstrate that ANX2 and PHB also interact in adipocytes. Mice lacking ANX2 have normal WAT vascularization, adipogenesis, and glucose metabolism but display WAT hypotrophy due to reduced fatty acid uptake by WAT endothelium and adipocytes. By using cell culture systems in which ANX2/PHB binding is disrupted either genetically or through treatment with a blocking peptide, we show that fatty acid transport efficiency relies on this protein complex. We also provide evidence that the interaction between ANX2 and PHB mediates fatty acid transport from the endothelium into adipocytes. Moreover, we demonstrate that ANX2 and PHB form a complex with the fatty acid transporter CD36. Finally, we show that the colocalization of PHB and CD36 on adipocyte surface is induced by extracellular fatty acids. Together, our results suggest that an unrecognized biochemical interaction between ANX2 and PHB regulates CD36-mediated fatty acid transport in WAT, thus revealing a new potential pathway for intervention in metabolic diseases.
我们之前已鉴定出抑制素（PHB）和膜联蛋白A2（ANX2）是在人类和小鼠白色脂肪组织（WAT）的血管内皮细胞表面相互作用的蛋白质。在此，我们证明ANX2和PHB在脂肪细胞中也相互作用。缺乏ANX2的小鼠具有正常的WAT血管生成、脂肪生成和葡萄糖代谢，但由于WAT内皮细胞和脂肪细胞对脂肪酸的摄取减少而表现出WAT萎缩。通过使用细胞培养系统，其中ANX2/PHB结合通过基因手段或用阻断肽处理而被破坏，我们表明脂肪酸转运效率依赖于这种蛋白质复合物。我们还提供证据表明ANX2和PHB之间的相互作用介导了脂肪酸从内皮细胞向内皮细胞的转运。此外，我们证明ANX2和PHB与脂肪酸转运蛋白CD36形成复合物。最后，我们表明细胞外脂肪酸可诱导PHB和CD36在脂肪细胞表面共定位。总之，我们的结果表明ANX2和PHB之间一种未被认识的生化相互作用调节了WAT中CD36介导的脂肪酸转运，从而揭示了一条干预代谢疾病的新潜在途径。
