Institute of Life Science 1, College of Medicine, Swansea University, Singleton Park, Swansea SA2 8PP, UK.
Institute of Life Science 1, College of Medicine, Swansea University, Singleton Park, Swansea SA2 8PP, UK.
Biochem Pharmacol. 2014 Aug 15;90(4):406-13. doi: 10.1016/j.bcp.2014.06.012. Epub 2014 Jun 20.
Endothelin-1 (ET-1) induces lipolysis in adipocytes, where ET-1 chronic exposure results in insulin resistance (IR) through suppression of glucose transporter (GLUT)4 translocation to the plasma membrane and consequently glucose uptake. ARF6 small GTPase, which plays a vital role in cell surface receptors trafficking, has previously been shown to regulate GLUT4 recycling and thereby insulin signalling. ARF6 also plays a role in ET-1 promoted endothelial cell migration. However, ARF6 involvement in ET-1-induced lipolysis in adipocytes is unknown. Therefore, we investigated the role of ARF6 in ET-1-induced lipolysis in 3T3-L1 adipocytes. This was achieved by studying the effect of inhibitors for the activation of ARF6 and other signalling proteins on ET-1 induced lipolysis and ARF6 activation in the adipocytes. Our results indicate that ET-1 induces, through endothelin type A receptor (ETAR), lipolysis, the ARF6 activation and extracellular-signal regulated kinase (ERK) phosphorylation in adipocytes, further ET-1 stimulated lipolysis is inhibited by the inhibitors of ARF6 activation, ERK phosphorylation and dynamin, which is essential for endocytosis. Our studies also revealed that ARF6 acts upstream of ERK in ET-1-indcued lipolysis. In summary, we determined that ET-1 activation of ETAR signalled through ARF6, which is crucial for lipolysis.
内皮素-1（ET-1）可诱导脂肪细胞中的脂肪分解，而 ET-1 的慢性暴露会通过抑制葡萄糖转运蛋白（GLUT）4向质膜的易位以及随后的葡萄糖摄取来导致胰岛素抵抗（IR）。ARF6 小 GTP 酶在细胞表面受体运输中起着至关重要的作用，先前已被证明可调节 GLUT4 的再循环，从而调节胰岛素信号。ARF6 还在 ET-1 促进内皮细胞迁移中发挥作用。然而，ARF6 在 ET-1 诱导的脂肪细胞脂肪分解中的作用尚不清楚。因此，我们研究了 ARF6 在 3T3-L1 脂肪细胞中 ET-1 诱导的脂肪分解中的作用。这是通过研究 ARF6 激活抑制剂和其他信号蛋白对 ET-1 诱导的脂肪分解和 ARF6 在脂肪细胞中的激活的影响来实现的。我们的结果表明，ET-1 通过内皮素 A 型受体（ETAR）诱导脂肪分解、ARF6 激活和细胞外信号调节激酶（ERK）磷酸化，进一步 ET-1 刺激的脂肪分解被 ARF6 激活抑制剂、ERK 磷酸化抑制剂和参与胞吞作用的 dynamin 抑制剂抑制。我们的研究还揭示了 ARF6 在 ET-1 诱导的脂肪分解中作为 ERK 的上游作用。总之，我们确定了 ET-1 通过 ARF6 激活 ETAR 信号传导，这对脂肪分解至关重要。
