Kahn A
Institut Cochin de Génétique moléculaire, Unité 129 de l'INSERM, CHU Cochin, Paris.
C R Seances Soc Biol Fil. 1998;192(5):813-27.
Glucose, that Claude Bernard has demonstrated in 1850 to be synthesized and secreted by the liver, is an important regulator of gene transcription in all types of organisms. In vertebrates, it especially regulates transcription of metabolic genes in the liver and fat tissue, activating genes encoding enzymes and regulators of the glycolytic and lipogenic pathways. Working with the L-type pyruvate kinase gene we have found that in hepatocytes glucose-dependent gene regulation requires: Presence of the GLUT2 glucose transporter, necessary to allow for an effective depletion in glucose 6-phosphate (G-6P) under gluconeogenic conditions. Phosphorylation of glucose to G-6P assured either by insulin-dependent glucokinase or by another hexokinase isoform. Most likely, entry of G-6P in the pentose phosphate pathway. Modulation of a kinase/phosphatase cascade, in particular inhibition of the 5'AMP-activated protein kinase. Signalling through a glucose response complex assembled onto a glucose-response element (GIRE) located in regulatory regions of glucose-responsive genes. The activators USF belong to the complex, and are required for a normal gene activation by glucose, as evidenced from the phenotype of knock-out mice deficient in USF. The study of USF-defective knock-out mice suggest that USF could be involved in nutritional activation of a whole class of genes regulated by glucose, and not by insulin itself. In particular, lipogenic genes and the ob gene, encoding the leptin satiety hormone, are abnormally responsive to diet in USF-/- mice. The transactivation potential of USF would be modulated by a glucose sensor system implying the COUP-TFII transcription inhibitor. The main role of insulin in the glucose response of genes like the L-PK gene is to induce the glucokinase gene. Glucagon, through cyclic AMP, inhibits L-PK gene transcription mainly through activation of PKA. The PKA catalytic subunit could act by phosphorylating member(s) of the glucose-response complex, or of contiguous transcription factor, e.g. HNF4. In conclusion, through a pluridisciplinary approach ranging from Claude Bernard-derived biology to modern molecular biology, important progress have been made during the last years on the mechanisms of the regulation of gene transcription by glucose in vertebrates.
1850年克劳德·伯纳德证明肝脏能合成并分泌葡萄糖，它是所有生物中基因转录的重要调节因子。在脊椎动物中，它尤其能调节肝脏和脂肪组织中代谢基因的转录，激活编码糖酵解和脂肪生成途径中酶及调节因子的基因。通过研究L型丙酮酸激酶基因，我们发现，在肝细胞中，葡萄糖依赖性基因调节需要：存在GLUT2葡萄糖转运体，这在糖异生条件下对有效消耗6-磷酸葡萄糖（G-6P）是必需的；通过胰岛素依赖性葡萄糖激酶或另一种己糖激酶同工型将葡萄糖磷酸化为G-6P；很可能是G-6P进入磷酸戊糖途径；调节激酶/磷酸酶级联反应，特别是抑制5'-AMP激活的蛋白激酶；通过组装在位于葡萄糖反应性基因调控区域的葡萄糖反应元件（GIRE）上的葡萄糖反应复合物进行信号传导。激活因子USF属于该复合物，并且是葡萄糖正常激活基因所必需的，这在缺乏USF的基因敲除小鼠的表型中得到了证明。对USF缺陷型基因敲除小鼠的研究表明，USF可能参与了由葡萄糖而非胰岛素本身调节的一整类基因的营养激活。特别是，脂肪生成基因和编码瘦素饱腹感激素的ob基因在USF-/-小鼠中对饮食的反应异常。USF的反式激活潜能将由一个涉及COUP-TFII转录抑制剂的葡萄糖传感器系统调节。胰岛素在L-PK基因等基因的葡萄糖反应中的主要作用是诱导葡萄糖激酶基因。胰高血糖素通过环磷酸腺苷，主要通过激活PKA来抑制L-PK基因转录。PKA催化亚基可能通过磷酸化葡萄糖反应复合物的成员或相邻转录因子（如HNF4）来发挥作用。总之，通过从克劳德·伯纳德时代的生物学发展到现代分子生物学的多学科方法，在过去几年里，脊椎动物中葡萄糖调节基因转录的机制取得了重要进展。
