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

• Antonio Gil-GÓmez ^[1] ; Ana Isabel Gómez-Sotelo ^[2] ; Isidora Ranchal ^[2] ; Ángela Rojas ^[1] ; Marta García-Valdecasas ^[1] ; Rocío Muñoz-Hernández ^[1] ; Rocío Gallego-Durán ^[1] ; Javier Ampuero ^[1] ; Manuel Romero Gómez ^[1]
  1. [1] Hospital Universitario Virgen del Rocío

     Hospital Universitario Virgen del Rocío

     Sevilla, España

     
  2. [2] Hospital Universitario de Valme

     Hospital Universitario de Valme

     Sevilla, España

     
• Localización: Revista Española de Enfermedades Digestivas, ISSN-e 2340-4167, ISSN 1130-0108, Vol. 110, Nº. 7, 2018, págs. 427-433
• Idioma: inglés
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• Resumen

  • 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.