Metformin modifies glutamine metabolism in an in vitro and in vivo model of hepatic encephalopathy
| Title: | Metformin modifies glutamine metabolism in an in vitro and in vivo model of hepatic encephalopathy |
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| Authors: | 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 |
| Source: | Revista Espanola de Enfermedades Digestivas, Vol 110, Iss 7, Pp 427-433 |
| Publisher Information: | Aran Ediciones. |
| Collection: | LCC:Diseases of the digestive system. Gastroenterology |
| Subject Terms: | Hepatic encephalopathy, Metformin, Ammonia, Glutaminase, Glutamine, Cirrhosis, ASCT2, mTOR, Porto-caval anastomosis, Diseases of the digestive system. Gastroenterology, RC799-869 |
| More Details: | 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. |
| Document Type: | article |
| File Description: | electronic resource |
| Language: | English Spanish; Castilian |
| ISSN: | 1130-0108 |
| Relation: | http://scielo.isciii.es/scielo.php?script=sci_arttext&pid=S1130-01082018000700004&lng=en&tlng=en; https://doaj.org/toc/1130-0108 |
| DOI: | 10.17235/reed.2018.5004/2017 |
| Access URL: | https://doaj.org/article/3fbc16d5de1e43f1aa42afc020cad1d4 |
| Accession Number: | edsdoj.3fbc16d5de1e43f1aa42afc020cad1d4 |
| Database: | Directory of Open Access Journals |
| ISSN: | 11300108 |
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| DOI: | 10.17235/reed.2018.5004/2017 |
| Published in: | Revista Espanola de Enfermedades Digestivas |
| Language: | English Spanish; Castilian |