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Low Hepatic Mg(2+) Content promotes Liver dysmetabolism: Implications for the Metabolic Syndrome.

Voma C, Etwebi Z, Soltani DA, Croniger C, Romani A - J Metab Syndr (2014)

Bottom Line: HepG2 cells cultured in low extracellular Mg(2+) presented a 20% decrease in total cellular Mg(2+) content, reduced glucose accumulation, and enhanced glucose 6-phosphate (G6P) transport into the endoplasmic reticulum (ER).The decrease in intrahepatic Mg(2+) content up-regulates G6P entry into the hepatic endoplasmic reticulum and its routing into the pentose shunt pathway for energetic purposes.The associated increased in NADPH production within the ER then stimulates cortisol production, setting the conditions for hepatic insulin resistance and further altering liver metabolism.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Biophysics, Case Western Reserve University, USA ; Department of Clinical Chemistry, Cleveland State University, USA.

ABSTRACT

Metabolic Syndrome, a pathological condition affecting approximately 35% of the USA population, is characterized by obesity, insulin resistance, and hypertension. Metabolic syndrome is considered the single most common condition predisposing to the development of various chronic diseases including diabetes and hypertension. Hypomagnesaemia has been consistently observed in association with metabolic syndrome, but it is unclear whether reduced Mg(2+) levels are the consequence or a possible cause for the development of the metabolic syndrome and/or its associated pathologies. Research performed in our laboratory showed that rats exposed for 2 weeks to a Mg(2+) deficient diet presented decreased glucose accumulation into the hepatocytes together with low Mg(2+) level in the circulation and within the liver cells. To better investigate the changes in glucose metabolism, HepG2 were used to mimic in vitro Mg(2+) deficiency conditions. HepG2 cells cultured in low extracellular Mg(2+) presented a 20% decrease in total cellular Mg(2+) content, reduced glucose accumulation, and enhanced glucose 6-phosphate (G6P) transport into the endoplasmic reticulum (ER). The increased G6P transport was associated with its enhanced hydrolysis by the glucose 6-phosphatase, but also conversion to 6-phosphogluconolactone by the glucose 6-phosphate dehydrogenase. The latter process resulted in the increased generation of NADPH within the ER and the increased conversion of cortisone to cortisol by the 11-β-hydroxysteroid dehydrogenase type-1 (11-β-OHSD1). Taken together, our results provide compelling evidence that Mg(2+) deficiency precedes and actually promotes some of the hepatic dysmetabolisms typical of the metabolic syndrome. The decrease in intrahepatic Mg(2+) content up-regulates G6P entry into the hepatic endoplasmic reticulum and its routing into the pentose shunt pathway for energetic purposes. The associated increased in NADPH production within the ER then stimulates cortisol production, setting the conditions for hepatic insulin resistance and further altering liver metabolism.

No MeSH data available.


Related in: MedlinePlus

Figure 5A. 0.6 mM HepG2 cells produced twice the amount of NADPH than 1 mM HepG2 cellsFigure 5. Glucose 6-phosphate dehydrogenase activity in HepG2 cells
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Figure 5: Figure 5A. 0.6 mM HepG2 cells produced twice the amount of NADPH than 1 mM HepG2 cellsFigure 5. Glucose 6-phosphate dehydrogenase activity in HepG2 cells

Mentions: To determine whether also this alternative pathway was enhanced in Mg2+ deficient cells, the production of NADPH was measured in HepG2 cells in the presence of various amounts of exogenous G6P. The results reported in Figure 5A indicate 0.6 mM HepG2 cells produced almost twice the amount of NADPH than 1 mM HepG2 cells. The NADPH production rate in 0.6 mM HepG2 cells was reduced by the addition of excess Mg2+ excess prior to G6P administration (Figure 5A) but not when a similar (Figure 5B) or a higher (not shown) dose of Mg2+ was added after the G6P administration and the NADPH production was already near maximal.


Low Hepatic Mg(2+) Content promotes Liver dysmetabolism: Implications for the Metabolic Syndrome.

Voma C, Etwebi Z, Soltani DA, Croniger C, Romani A - J Metab Syndr (2014)

Figure 5A. 0.6 mM HepG2 cells produced twice the amount of NADPH than 1 mM HepG2 cellsFigure 5. Glucose 6-phosphate dehydrogenase activity in HepG2 cells
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4403798&req=5

Figure 5: Figure 5A. 0.6 mM HepG2 cells produced twice the amount of NADPH than 1 mM HepG2 cellsFigure 5. Glucose 6-phosphate dehydrogenase activity in HepG2 cells
Mentions: To determine whether also this alternative pathway was enhanced in Mg2+ deficient cells, the production of NADPH was measured in HepG2 cells in the presence of various amounts of exogenous G6P. The results reported in Figure 5A indicate 0.6 mM HepG2 cells produced almost twice the amount of NADPH than 1 mM HepG2 cells. The NADPH production rate in 0.6 mM HepG2 cells was reduced by the addition of excess Mg2+ excess prior to G6P administration (Figure 5A) but not when a similar (Figure 5B) or a higher (not shown) dose of Mg2+ was added after the G6P administration and the NADPH production was already near maximal.

Bottom Line: HepG2 cells cultured in low extracellular Mg(2+) presented a 20% decrease in total cellular Mg(2+) content, reduced glucose accumulation, and enhanced glucose 6-phosphate (G6P) transport into the endoplasmic reticulum (ER).The decrease in intrahepatic Mg(2+) content up-regulates G6P entry into the hepatic endoplasmic reticulum and its routing into the pentose shunt pathway for energetic purposes.The associated increased in NADPH production within the ER then stimulates cortisol production, setting the conditions for hepatic insulin resistance and further altering liver metabolism.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Biophysics, Case Western Reserve University, USA ; Department of Clinical Chemistry, Cleveland State University, USA.

ABSTRACT

Metabolic Syndrome, a pathological condition affecting approximately 35% of the USA population, is characterized by obesity, insulin resistance, and hypertension. Metabolic syndrome is considered the single most common condition predisposing to the development of various chronic diseases including diabetes and hypertension. Hypomagnesaemia has been consistently observed in association with metabolic syndrome, but it is unclear whether reduced Mg(2+) levels are the consequence or a possible cause for the development of the metabolic syndrome and/or its associated pathologies. Research performed in our laboratory showed that rats exposed for 2 weeks to a Mg(2+) deficient diet presented decreased glucose accumulation into the hepatocytes together with low Mg(2+) level in the circulation and within the liver cells. To better investigate the changes in glucose metabolism, HepG2 were used to mimic in vitro Mg(2+) deficiency conditions. HepG2 cells cultured in low extracellular Mg(2+) presented a 20% decrease in total cellular Mg(2+) content, reduced glucose accumulation, and enhanced glucose 6-phosphate (G6P) transport into the endoplasmic reticulum (ER). The increased G6P transport was associated with its enhanced hydrolysis by the glucose 6-phosphatase, but also conversion to 6-phosphogluconolactone by the glucose 6-phosphate dehydrogenase. The latter process resulted in the increased generation of NADPH within the ER and the increased conversion of cortisone to cortisol by the 11-β-hydroxysteroid dehydrogenase type-1 (11-β-OHSD1). Taken together, our results provide compelling evidence that Mg(2+) deficiency precedes and actually promotes some of the hepatic dysmetabolisms typical of the metabolic syndrome. The decrease in intrahepatic Mg(2+) content up-regulates G6P entry into the hepatic endoplasmic reticulum and its routing into the pentose shunt pathway for energetic purposes. The associated increased in NADPH production within the ER then stimulates cortisol production, setting the conditions for hepatic insulin resistance and further altering liver metabolism.

No MeSH data available.


Related in: MedlinePlus