Selectively increased expression of the astrocytic/endothelial glucose transporter protein GLUT1 in acute liver failure

Acute liver failure (ALF) is consistently accompanied by alterations in brain energy metabolites and recent nuclear magnetic resonance (NMR) studies suggest disturbances in brain oxidative metabolism in experimental ALF. Glucose transport across the blood-brain barrier is essential to sustain brain energy metabolism and is accomplished by the facilitative glucose transporter GLUT1. To investigate alterations in brain glucose uptake in acute liver failure further, GLUT1 expression and [14C]-2-deoxy-D-glucose uptake were measured in the brains of rats with hepatic devascularization. RT-PCR and Western blot analyses showed significant increases in steady-state levels of GLUT1 mRNA and protein in frontal cortex as early as 6 h following hepatic devascularization, (prior to the onset of brain edema and encephalopathy) which remained elevated at coma stages of encephalopathy. Expression of the astrocytic (45-kDa) and endothelial (55-kDa) forms of GLUT1 was increased as a result of hepatic devascularization. Exposure of cultured astrocytes to pathophysiologically relevant concentrations of ammonia resulted in increased GLUT1 expression, suggesting that elevated ammonia levels are responsible for GLUT1 upregulation in ALF. Increased GLUT1 expression in ALF was selective, since expression of the neuronal glucose transporter GLUT3 and other glucose-regulated proteins (GRP-78 and GRP-94) was unaltered. [14C]-2-deoxy-D-glucose autoradiography revealed increases in cerebral glucose uptake following the induction of GLUT1 in ALF. These results suggest that ammonia-induced increases of GLUT1 expression resulting in increased cerebral glucose uptake occur in ALF and could contribute to the pathophysiological mechanisms responsible for the neurological complications of this condition.