PDF(Pubmed)
Abstract：
Iron is often accumulated in the liver during pathological conditions such as cirrhosis and cancer. Elevated expression of glucose transporters GLUT1 and GLUT3 is associated with reduced overall survival in patients with hepatocellular carcinoma. However, it is not known whether iron can regulate glucose transporters and contribute to tumor proliferation. In the present study, we found that treatment of human liver cell line HepG2 with ferric ammonium citrate (FAC) resulted in a significant upregulation of GLUT3 mRNA and protein in a dose-dependent manner. Similarly, iron accumulation in mice fed with high dietary iron as well as in mice injected intraperitoneally with iron dextran enhanced the GLUT3 expression drastically in the liver. We demonstrated that iron-induced hepatic GLUT3 upregulation is mediated by the LKB1/AMPK/CREB1 pathway, and this activation was reversed when treated with iron chelator deferiprone. In addition, inhibition of GLUT3 using siRNA prevented iron-mediated increase in the expression of cell cycle markers and cellular hyperproliferation. Furthermore, exogenous sodium beta-hydroxybutyrate treatment prevented iron-mediated hepatic GLUT3 activation both in vitro and in vivo. Together, these results underscore the importance of iron, AMPK, CREB1 and GLUT3 pathways in cell proliferation and highlight the therapeutic potential of sodium beta-hydroxybutyrate in hepatocellular carcinoma with high GLUT3 expression.
摘要：
在肝硬化和癌症等病理状况期间，铁通常在肝脏中积累。葡萄糖转运蛋白GLUT1和GLUT3的表达升高与肝细胞癌患者总生存率降低相关.然而,目前尚不清楚铁是否可以调节葡萄糖转运蛋白并促进肿瘤增殖。在本研究中,我们发现,用柠檬酸铁铵(FAC)处理人肝细胞HepG2导致GLUT3mRNA和蛋白呈剂量依赖性的显著上调.同样，高饮食铁喂养的小鼠以及腹膜内注射右旋糖酐铁的小鼠中的铁积累急剧增强了肝脏中的GLUT3表达。我们证明铁诱导的肝GLUT3上调是由LKB1/AMPK/CREB1途径介导的，当用铁螯合剂去铁酮处理时，这种激活被逆转。此外,使用siRNA抑制GLUT3可防止铁介导的细胞周期标志物表达增加和细胞过度增殖。此外，外源性β-羟基丁酸钠治疗可在体内和体外阻止铁介导的肝GLUT3激活.一起,这些结果强调了铁的重要性，AMPK,CREB1和GLUT3通路在细胞增殖中的作用，并突出β-羟基丁酸钠在GLUT3高表达的肝细胞癌中的治疗潜力。
