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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

Glucose disappearance from the culture medium (Figure 2A) and glucose accumulation (Figure 2B) in HepG2 cells cultured in the presence of 0.6 mM or 1 mM external Mg2+.
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Figure 2: Glucose disappearance from the culture medium (Figure 2A) and glucose accumulation (Figure 2B) in HepG2 cells cultured in the presence of 0.6 mM or 1 mM external Mg2+.

Mentions: Our and others laboratories [13,16] have previously reported that a reduction in extracellular Mg2+ concentration impairs glucose accumulation into the cells. To determine whether the reduction in ATP content depended on a reduced transport of glucose into the cells, we measured the changes in medium glucose content at 24 hour intervals by glucose enzymatic kit. Our results indicated that HepG2 cells in 0.6 mM [Mg2+]o accumulated approximated 50% less glucose than HepG2 cells in 1 mM [Mg2+] (Figure 2A). Because the reduced glucose utilization could depend on changes in the number of cells and their reduplication rate, we measured glucose transport into the cells by 3H-2-deoxy-glucose radio-isotopic distributions, normalized per number of cells. As Figure 2B shows, 0.6 mM HepG2 cells accumulated less glucose (~85%) than 1 mM HepG2 cells under basal conditions. The glucose accumulation rate in 0.6 mM HepG2 cells did not increase upon administration of 10 nM insulin (Figure 2B), whereas it increased significantly in 1 mM HepG2 cells. Similar results were obtained when glucose was labelled with 3H-3-methyl-glucose or 14C-glucose (data not shown), or when glucose concentrations higher than 100 μM were used (data now shown).


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)

Glucose disappearance from the culture medium (Figure 2A) and glucose accumulation (Figure 2B) in HepG2 cells cultured in the presence of 0.6 mM or 1 mM external Mg2+.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Glucose disappearance from the culture medium (Figure 2A) and glucose accumulation (Figure 2B) in HepG2 cells cultured in the presence of 0.6 mM or 1 mM external Mg2+.
Mentions: Our and others laboratories [13,16] have previously reported that a reduction in extracellular Mg2+ concentration impairs glucose accumulation into the cells. To determine whether the reduction in ATP content depended on a reduced transport of glucose into the cells, we measured the changes in medium glucose content at 24 hour intervals by glucose enzymatic kit. Our results indicated that HepG2 cells in 0.6 mM [Mg2+]o accumulated approximated 50% less glucose than HepG2 cells in 1 mM [Mg2+] (Figure 2A). Because the reduced glucose utilization could depend on changes in the number of cells and their reduplication rate, we measured glucose transport into the cells by 3H-2-deoxy-glucose radio-isotopic distributions, normalized per number of cells. As Figure 2B shows, 0.6 mM HepG2 cells accumulated less glucose (~85%) than 1 mM HepG2 cells under basal conditions. The glucose accumulation rate in 0.6 mM HepG2 cells did not increase upon administration of 10 nM insulin (Figure 2B), whereas it increased significantly in 1 mM HepG2 cells. Similar results were obtained when glucose was labelled with 3H-3-methyl-glucose or 14C-glucose (data not shown), or when glucose concentrations higher than 100 μM were used (data now shown).

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