Reduced cellular Mg2+ content enhances hexose 6-phosphate dehydrogenase activity and expression in HepG2 and HL-60 cells

• Total and compartmentalized cellular Mg2+ decreases in cell exposed to low [Mg2+]o.
• Decreased cytosolic Mg2+ favors G6P entry into the E.R. and its oxidation by H6PD.
• This oxidation increases intra-reticular NADPH content for other metabolic pathways.
• H6PD gene and protein expression increase in cells grown in low [Mg2+]o conditions.
• Cytoplasmic Mg2+ regulates G6P utilization by reticular H6PD.

We have reported that Mg2+ dynamically regulates glucose 6-phosphate entry into the endoplasmic reticulum and its hydrolysis by the glucose 6-phosphatase in liver cells. In the present study, we report that by modulating glucose 6-phosphate entry into the endoplasmic reticulum of HepG2 cells, Mg2+ also regulates the oxidation of this substrate via hexose 6-phosphate dehydrogenase (H6PD). This regulatory effect is dynamic as glucose 6-phosphate entry and oxidation can be rapidly down-regulated by the addition of exogenous Mg2+. In addition, HepG2 cells growing in low Mg2+ show a marked increase in hexose 6-phosphate dehydrogenase mRNA and protein expression. Metabolically, these effects on hexose 6-phosphate dehydrogenase are important as this enzyme increases intra-reticular NADPH production, which favors fatty acid and cholesterol synthesis. Similar effects of Mg2+ were observed in HL-60 cells.These and previously published results suggest that in an hepatocyte culture model changes in cytoplasmic Mg2+ content regulates glucose 6-phosphate utilization via glucose 6 phosphatase and hexose-6 phosphate dehydrogenase in alternative to glycolysis and glycogen synthesis. This alternative regulation might be of relevance in the transition from fed to fasted state.

Figure optionsDownload high-quality image (131 K)Download as PowerPoint slide