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La gluconeogénesis hepática regulada por insulina a través de la interacción FOXO1-PGC-1alpha
Pere Puigserver1, James Rhee, Jerry Donovan
1Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Nature
|May 20, 2003
Resumen
La gluconeogénesis hepática, esencial para la supervivencia en ayunas, está regulada por FOXO1 y PGC-1alpha. Estos factores interactúan para controlar la producción de glucosa regulada por insulina en el hígado.
Área de la Ciencia:
- Regulación del metabolismo.
- Biología molecular La biología molecular.
- Endocrinología Endocrinología.
Sus antecedentes:
- La gluconeogénesis hepática es vital para la supervivencia durante el ayuno, pero está desregulada en la diabetes.
- Los glucocorticoides y el glucagón estimulan la gluconeogénesis hepática, mientras que la insulina la suprime.
- FOXO1 y PGC-1alpha son reguladores clave, pero su interacción no estaba clara.
Objetivo del estudio:
- Para aclarar el mecanismo de colaboración entre FOXO1 y PGC-1alpha en la regulación de la gluconeogénesis hepática.
- Para investigar el papel de la fosforilación mediada por Akt en la interacción FOXO1-PGC-1alpha.
- Para determinar el impacto de la insulina en la gluconeogénesis estimulada por PGC-1alpha a través de FOXO1.1.
Principales métodos:
- Utilizó alelos FOXO1 de tipo salvaje y mutantes en modelos celulares y de ratón.
- Se ha investigado la unión al PGC-1alfa y la coactivación de FOXO1.1.
- Evaluó el efecto de la insulina en la gluconeogénesis estimulada por PGC-1alpha en presencia de FOXO1.1 modificado.
Principales resultados:
- PGC-1alpha se une y coactiva FOXO1, un proceso inhibido por la fosforilación de Akt.
- FOXO1 es esencial para la inducción mediada por PGC-1alpha de la expresión génica gluconeogénica.
- La supresión de la gluconeogénesis inducida por PGC-1alpha por la insulina es revertida por los mutantes FOXO1 insensibles a la insulina.
Conclusiones:
- FOXO1 y PGC-1alpha forman un complejo crítico para ejecutar la gluconeogénesis hepática regulada por insulina.
- Esta interacción pone de relieve una vía clave para controlar la producción de glucosa.
- Dirigirse a la interacción FOXO1-PGC-1alpha puede ofrecer estrategias terapéuticas para los trastornos metabólicos.
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