Takigawa-Imamura Hisako, Sekine Takumi, Murata Mitsuo, Takayama Kiyoshi, Nakazawa Kiyoshi, Nakagawa Junichi
Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
Biosci Biotechnol Biochem. 2003 Jul;67(7):1499-506. doi: 10.1271/bbb.67.1499.
Glucose incorporation is regulated mainly by GLUT4 in skeletal muscles. Here we report that treatment of L6 myotubes with scriptide, a hydroxamic acid-based histone deacetylase (HDAC) inhibitor, stimulated 2-deoxyglucose uptake. The effect appeared only after 24 hr, resulting in 2.4-fold glucose uptake at treatment day 6. Scriptide acted synergistically with insulin, indicating it stimulated a distinct pathway from the insulin signaling pathway. It was not observed in undifferentiated myoblasts or 3T3-L1 adipocytes, suggesting a muscle-specific effect of scriptide. A five-carbon chain and hydroxamic acid, essential for histone deacetylase inhibition, were indispensable for this effect, and trichostatin A stimulated glucose uptake as well. Scriptide increased the cellular content of GLUT4, and induced GLUT4 translocation, but GLUT4 mRNA level did not change, indicating scriptide functions posttranslationally. Our results indicated a novel function for HDAC inhibitors of increasing GLUT4 content and its translocation in muscle cells, resulting in stimulation of glucose uptake.
葡萄糖摄取主要由骨骼肌中的GLUT4调节。在此我们报告，用Scriptide（一种基于异羟肟酸的组蛋白脱乙酰酶（HDAC）抑制剂）处理L6肌管，可刺激2-脱氧葡萄糖摄取。这种效应仅在24小时后出现，在处理第6天时导致葡萄糖摄取增加2.4倍。Scriptide与胰岛素协同作用，表明它刺激了一条与胰岛素信号通路不同的途径。在未分化的成肌细胞或3T3-L1脂肪细胞中未观察到这种效应，提示Scriptide具有肌肉特异性作用。对组蛋白脱乙酰酶抑制至关重要的五碳链和异羟肟酸对这种效应不可或缺，曲古抑菌素A也能刺激葡萄糖摄取。Scriptide增加了GLUT4的细胞含量，并诱导了GLUT4易位，但GLUT4 mRNA水平没有变化，表明Scriptide在翻译后发挥作用。我们的结果表明HDAC抑制剂具有增加肌肉细胞中GLUT4含量及其易位的新功能，从而刺激葡萄糖摄取。
