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Metformin modifies glutamine metabolism in an in vitro and in vivo model of hepatic encephalopathy.

Metformin modifies glutamine metabolism in an in vitro and in vivo model of hepatic encephalopathy.
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Gil-Gomez A, Gómez-Sotelo AI, Ranchal I, Rojas Á, García-Valdecasas M, Muñoz-Hernández R, Gallego-Durán R, Ampuero J, Romero Gómez M,


Gil-Gomez A, Gómez-Sotelo AI, Ranchal I, Rojas Á, García-Valdecasas M, Muñoz-Hernández R, Gallego-Durán R, Ampuero J, Romero Gómez M, (click to view)

Gil-Gomez A, Gómez-Sotelo AI, Ranchal I, Rojas Á, García-Valdecasas M, Muñoz-Hernández R, Gallego-Durán R, Ampuero J, Romero Gómez M,

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Revista espanola de enfermedades digestivas : organo oficial de la Sociedad Espanola de Patologia Digestiva 2018 03 15110() doi 10.17235/reed.2018.5004/2017
Abstract
AIM
to analyze the effect of metformin on ammonia production derived from glutamine metabolism in vitro and in vivo.

METHODS
twenty male Wistar rats were studied for 28 days after a porto-caval anastomosis (n = 16) or a sham operation (n = 4). Porto-caval shunted animals were randomized into two groups (n = 8) and either received 30 mg/kg/day of metformin for two weeks or were control animals. Plasma ammonia concentration, Gls gene expression and K-type glutaminase activity were measured in the small intestine, muscle and kidney. Furthermore, Caco2 were grown in different culture media containing glucose/glutamine as the main carbon source and exposed to different concentrations of the drug. The expression of genes implicated in glutamine metabolism were analyzed.

RESULTS
metformin was associated with a significant inhibition of glutaminase activity levels in the small intestine of porto-caval shunted rats (0.277 ± 0.07 IU/mg vs 0.142 ± 0.04 IU/mg) and a significant decrease in plasma ammonia (204.3 ± 24.4 µg/dl vs 129.6 ± 16.1 µg/dl). Glucose withdrawal induced the expression of the glutamine transporter SLC1A5 (2.54 ± 0.33 fold change; p < 0.05). Metformin use reduced MYC levels in Caco2 and consequently, SLC1A5 and GLS expression, with a greater effect in cells dependent on glutaminolytic metabolism. CONCLUSION
metformin regulates ammonia homeostasis by modulating glutamine metabolism in the enterocyte, exerting an indirect control of both the uptake and degradation of glutamine. This entails a reduction in the production of metabolites and energy through this pathway and indirectly causes a decrease in ammonia production that could be related to a decreased risk of HE development.

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