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Published on: June 9, 2019
Reduced cellular Mg²⁺ content enhances hexose 6-phosphate dehydrogenase activity and expression in HepG2 and HL-60
Chesinta Voma1, Andrew Barfell2, Colleen Croniger3
1Department of Physiology and Biophysics, Case Western Reserve University, USA; Department of Clinical Chemistry, Cleveland State University, USA.
Abstract:
We have reported that Mg(2+) 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, Mg(2+) 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 Mg(2+). In addition, HepG2 cells growing in low Mg(2+) 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 Mg(2+) were observed in HL-60 cells. These and previously published results suggest that in an hepatocyte culture model changes in cytoplasmic Mg(2+) 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.
Insights
Magnesium ions (Mg2+) dynamically regulate glucose metabolism in liver cells. This study shows Mg2+ controls glucose-6-phosphate entry and oxidation, impacting NADPH production for fatty acid synthesis.
Area of Science:
- Biochemistry
- Cell Biology
- Metabolic Regulation
Background:
- Magnesium ions (Mg2+) are crucial intracellular cations involved in numerous cellular processes.
- Mg2+ has been shown to regulate glucose-6-phosphatase activity in liver cells.
- The role of Mg2+ in other glucose-6-phosphate metabolic pathways remains less understood.
Purpose of the Study:
- To investigate the regulatory role of Mg2+ on glucose-6-phosphate oxidation via hexose-6-phosphate dehydrogenase (H6PD) in liver cells.
- To explore the impact of Mg2+ on H6PD expression and its metabolic consequences.
Main Methods:
- Utilized HepG2 and HL-60 cell lines.
- Assessed the effect of Mg2+ on glucose-6-phosphate entry into the endoplasmic reticulum.
- Measured H6PD activity, mRNA, and protein expression.
- Analyzed intra-reticular NADPH production.
Main Results:
- Mg2+ dynamically regulates glucose-6-phosphate entry into the endoplasmic reticulum and its subsequent oxidation by H6PD.
- Exogenous Mg2+ rapidly down-regulates glucose-6-phosphate entry and oxidation.
- Low extracellular Mg2+ leads to increased H6PD mRNA and protein expression in HepG2 cells.
- Mg2+-mediated regulation of H6PD increases intra-reticular NADPH, favoring fatty acid and cholesterol synthesis.
Conclusions:
- Cytoplasmic Mg2+ content modulates glucose-6-phosphate utilization through both glucose-6-phosphatase and H6PD pathways in hepatocytes.
- This Mg2+-dependent regulation provides an alternative to glycolysis and glycogen synthesis.
- This metabolic regulation may be significant during the transition between fed and fasted states.
