Year 2018 / Volume 110 / Number 7
Original
Metformin modifies glutamine metabolism in an in vitro and in vivo model of hepatic encephalopathy

427-433

DOI: 10.17235/reed.2018.5004/2017

Antonio Gil-GÓmez, Ana Isabel Gómez-Sotelo, Isidora Ranchal, Ángela Rojas, Marta García-Valdecasas, Rocío Muñoz-Hernández, Rocío Gallego-Durán, Javier Ampuero, Manuel Romero Gómez,

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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03/05/2020 8:09:04
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Gil-GÓmez A, Gómez-Sotelo A, Ranchal I, Rojas Á, García-Valdecasas M, Muñoz-Hernández R, et all. Metformin modifies glutamine metabolism in an in vitro and in vivo model of hepatic encephalopathy. 5004/2017


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Publication history

Received: 11/04/2017

Accepted: 01/02/2018

Online First: 15/03/2018

Published: 02/07/2018

Article revision time: 289 days

Article Online First time: 338 days

Article editing time: 447 days


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