Institutes of Cellular Medicine and Ageing and Health, Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH United Kingdom; email:
Annu Rev Nutr. 2016 Jul 17;36:389-415. doi: 10.1146/annurev-nutr-071715-051145. Epub 2016 May 4.
Liver glucose metabolism is dependent on glucokinase activity. Glucokinase expression is transcriptionally regulated by hormones and metabolites of glucose, and glucokinase activity is dependent on reversible binding of glucokinase to a specific inhibitor protein, glucokinase regulatory protein (GKRP), and to other binding proteins such as 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase (PFK2/FBP2), which functions as an activator. Glucokinase is inhibited in the postabsorptive state by sequestration in the nucleus bound to GKRP, and it is activated postprandially by portal hyperglycemia and fructose through dissociation from GKRP, translocation to the cytoplasm, and binding to PFK2/FBP2. Glucagon dissociates this interaction, promoting translocation back to the nucleus. In humans, changes in glucokinase expression and activity are associated with poorly controlled type 2 diabetes and with nonalcoholic fatty liver disease, and a common variant of GKRP with altered binding affinity for glucokinase is associated with increased blood and liver lipids and other metabolic traits that implicate a role for GKRP in maintaining intrahepatic metabolite homeostasis.
肝葡萄糖代谢依赖于葡萄糖激酶的活性。葡萄糖激酶的表达受激素和葡萄糖代谢物的转录调控，其活性依赖于葡萄糖激酶与特定抑制剂蛋白葡萄糖激酶调节蛋白（GKRP）的可逆结合，以及与其他结合蛋白（如 6-磷酸果糖-2-激酶/果糖 2,6-二磷酸酶（PFK2/FBP2））的结合，后者作为激活剂发挥作用。在吸收后状态下，葡萄糖激酶通过与 GKRP 结合而被隔离在核内而被抑制，餐后通过门静脉高血糖和果糖从 GKRP 解离、转位到细胞质以及与 PFK2/FBP2 结合而被激活。胰高血糖素使这种相互作用解离，促进转位回核内。在人类中，葡萄糖激酶表达和活性的变化与 2 型糖尿病控制不佳以及非酒精性脂肪性肝病有关，而 GKRP 的常见变异与葡萄糖激酶结合亲和力改变有关，这与血液和肝脏脂质以及其他代谢特征增加有关，这些特征表明 GKRP 在维持肝内代谢物平衡方面发挥作用。
