Zhang J Z, Behrooz A, Ismail-Beigi F
Physiology and Biophysics, Case Western Reserve University, Cleveland, OH, USA.
Am J Kidney Dis. 1999 Jul;34(1):189-202. doi: 10.1016/s0272-6386(99)70131-9.
Transport of glucose into most mammalian cells and tissues is rate-controlling for its metabolism. Glucose transport is acutely stimulated by hypoxic conditions, and the response is mediated by enhanced function of the facilitative glucose transporters (Glut), Glut1, Glut3, and Glut4. The expression and activity of the Glut-mediated transport is coupled to the energetic status of the cell, such that the inhibition of oxidative phosphorylation resulting from exposure to hypoxia leads to a stimulation of glucose transport. The premise that the glucose transport response to hypoxia is secondary to inhibition of mitochondrial function is supported by the finding that exposure of a variety of cells and tissues to agents such as azide or cyanide, in the presence of oxygen, also leads to stimulation of glucose transport. The mechanisms underlying the acute stimulation of transport include translocation of Gluts to the plasma membrane (Glut1 and Glut4) and activation of transporters pre-exiting in the plasma membrane (Glut1). A more prolonged exposure to hypoxia results in enhanced transcription of the Glut1 glucose transporter gene, with little or no effect on transcription of other Glut genes. The transcriptional effect of hypoxia is mediated by dual mechanisms operating in parallel, namely, (1) enhancement of Glut1 gene transcription in response to a reduction in oxygen concentration per se, acting through the hypoxia-signaling pathway, and (2) stimulation of Glut1 transcription secondary to the associated inhibition of oxidative phosphorylation during hypoxia. Among the various hypoxia-responsive genes, Glut1 is the first gene whose rate of transcription has been shown to be dually regulated by hypoxia. In addition, inhibition of oxidative phosphorylation per se, and not the reduction in oxygen tension itself, results in a stabilization of Glut1 mRNA. The increase in cell Glut1 mRNA content, resulting from its enhanced transcription and decreased degradation, leads to increased cell and plasma membrane Glut1 content, which is manifested by a further stimulation of glucose transport during the adaptive response to prolonged exposure to hypoxia.
葡萄糖进入大多数哺乳动物细胞和组织的过程是其代谢的速率控制环节。缺氧条件可急性刺激葡萄糖转运，该反应由易化葡萄糖转运体（Glut）Glut1、Glut3和Glut4功能增强介导。Glut介导的转运的表达和活性与细胞的能量状态相关联，因此暴露于缺氧环境导致的氧化磷酸化抑制会刺激葡萄糖转运。葡萄糖转运对缺氧的反应继发于线粒体功能抑制这一前提得到了以下发现的支持：在有氧存在的情况下，将多种细胞和组织暴露于叠氮化物或氰化物等试剂中也会导致葡萄糖转运受到刺激。转运急性刺激的潜在机制包括Gluts转位至质膜（Glut1和Glut4）以及激活预先存在于质膜中的转运体（Glut1）。更长时间暴露于缺氧环境会导致Glut1葡萄糖转运体基因转录增强，而对其他Glut基因的转录几乎没有影响。缺氧的转录效应由并行运作的双重机制介导，即：（1）响应氧浓度本身的降低，通过缺氧信号通路增强Glut1基因转录；（2）缺氧期间氧化磷酸化相关抑制继发刺激Glut1转录。在各种缺氧反应基因中，Glut1是首个转录速率被证明受缺氧双重调节的基因。此外，氧化磷酸化本身的抑制而非氧张力的降低导致Glut1 mRNA稳定。由于转录增强和降解减少导致细胞Glut1 mRNA含量增加，进而导致细胞和质膜Glut1含量增加，这在对长时间暴露于缺氧的适应性反应中表现为葡萄糖转运进一步受到刺激。
