Metformin modifies glutamine metabolism in an in vitro and in vivo model of hepatic encephalopathy
| Autor: | Gil Gómez, Antonio, Gómez-Sotelo, Ana Isabel, Ranchal Illescas, Isidora, Rojas Álvarez, M. Ángeles de, García-Valdecasas Merino, Marta María, Muñoz Hernández, Rocío, Ampuero Herrojo, Javier, Romero Gómez, Manuel |
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| Přispěvatelé: | Universidad de Sevilla. Departamento de Medicina, Universidad de Sevilla. Departamento de Farmacia y Tecnología Farmacéutica, Universidad de Sevilla. CTS532: Unidad de Hepatología |
| Rok vydání: | 2018 |
| Předmět: | |
| Zdroj: | idUS: Depósito de Investigación de la Universidad de Sevilla Universidad de Sevilla (US) idUS. Depósito de Investigación de la Universidad de Sevilla instname |
| Popis: | 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. Junta de Andalucía. Consejería de Innovación, Ciencia y Empresa PIE-CTS-7991 |
| Databáze: | OpenAIRE |
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