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Las alteraciones en el metabolismo de un carbono en la disfunción metabólica asociada a la enfermedad hepática
Mikkel Parsberg Werge1, Adrian McCann2, Elias Badal Rashu1
1Gastro Unit, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark.
Annals of hepatology
|September 1, 2025
Resumen
La disfunción metabólica en la enfermedad del hígado graso (MASLD) implica un metabolismo alterado de un carbono. El tratamiento con semaglutida revirtió estos cambios en un modelo de ratón, lo que sugiere un potencial terapéutico para la enfermedad.
Área de la Ciencia:
- La bioquímica
- Metabolomía
- La genómica
Sus antecedentes:
- Los trastornos del metabolismo de un carbono (OCM) están implicados en las enfermedades cardiometabólicas.
- La enfermedad hepática grasa no alcohólica (NAFLD) y su forma progresiva, la esteatohepatitis asociada a la disfunción metabólica (MASH, por sus siglas en inglés), representan un problema de salud mundial cada vez mayor.
- Comprender las bases metabólicas de MASLD es crucial para desarrollar tratamientos efectivos.
Objetivo del estudio:
- Investigar las alteraciones de los metabolitos y enzimas de la OCM en pacientes con MASLD.
- Evaluar el impacto de la semaglutida en la MCO en un modelo de ratón MASH inducido por la dieta.
Principales métodos:
- Metabolomía dirigida y transcriptomía a granel en muestras de plasma y hígado de 100 pacientes con MASLD y 50 controles.
- Metabolómicas y transcriptómicas no dirigidas en el hígado y el plasma de ratones con obesidad inducida por la dieta y MASH (DIO-MASH) tratados con semaglutida o vehículo.
- Análisis de los niveles de folato, vitamina B6, betaína, serina, glicina y glutamato, junto con las actividades de las enzimas clave.
Principales resultados:
- Los pacientes con MASLD presentaron concentraciones alteradas de metabolitos de la OCM (folato, vitamina B6, betaína, serina, glicina) y niveles elevados de homocisteína y glutamato, lo que indica una alteración de la transsulfuración y de los ciclos metionina/folato.
- Estos cambios metabólicos se correlacionaron con actividades enzimáticas alteradas y se reflejaron en ratones DIO-MASH.
- El tratamiento con semaglutida en ratones DIO-MASH redujo el peso corporal, la inflamación hepática y la fibrosis, y revirtió en gran medida las alteraciones metabólicas y de expresión génica observadas.
Conclusiones:
- El MASLD está asociado con alteraciones significativas en los metabolitos y enzimas de la OCM.
- Los cambios metabólicos observados en pacientes con MASLD fueron recapitulados en un modelo de ratón preclínico.
- La semaglutida demostró eficacia para revertir estas alteraciones metabólicas y mejorar la patología hepática en el modelo de ratón MASH.
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