G6PT inhibition model using HL-60 cells and induction of ROS production through PKC/NOX2 activation: Clinical condition for elucidation of glycogen storage disease type Ib

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Glycogen storage disease type Ib (GSD-Ib) is caused by mutations in the glucose-6-phosphate transporter (G6PT) gene, which is involved in glycogen metabolism. Patients with GSD-Ib are known to develop neutropenia as a specific symptom, but the causes remain unclear. To elucidate NAD(P)H oxidase (NOX) 2-associated mechanisms in neutrophil cell membranes, we examined the mechanism of reactive oxygen species (ROS) production after differentiation from HL-60 cells, and the collapse of glycogen metabolism because of G6PT deficiency. ROS production and caspase-3 and -9 activation were observed in G6PT inhibitor-treated neutrophils but not in control cells. Suppression of ROS production by NOX2 inhibitors or protein kinase C (PKC) inhibitors combined with G6PT inhibitor was found to be dependent on the concentration of each inhibitor. Furthermore, ROS production, and caspase-3 and -9 activities were dependent on glucose concentrations. These data indicate that reduced ROS production and suppressed apoptosis in the presence of PKC inhibitors may reflect suppression of PKC-induced NOX2 activation. However, under low glucose conditions, ROS production was reduced and apoptosis was suppressed in neutrophils, suggesting that glucose is a substrate for initiating ROS production. In the present study, the investigation of the pathology of GSD-Ib indicated that a high intracellular glucose level leads to an increase in ROS production by PKC induction and NOX2 activation.

G6PT inhibition model using HL-60 cells and induction of ROS production through PKC/NOX2 activation: Clinical condition for elucidation of glycogen storage disease type Ib

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