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El coactivador CREB CRTC2 vincula el estrés hepático ER y la gluconeogénesis en ayunas
Yiguo Wang1, Liliana Vera, Wolfgang H Fischer
1Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
Nature
|June 23, 2009
Resumen
El coactivador de transcripción regulado por CREB 2 (CRTC2) actúa como un sensor dual para el ayuno y el estrés en el retículo endoplasmático (ER). El estrés ER, a través de ATF6alpha, puede reducir la producción de glucosa hepática, lo que afecta la homeostasis de la glucosa.
Área de la Ciencia:
- El metabolismo es el metabolismo.
- Biología celular Biología celular.
- Endocrinología Endocrinología.
Sus antecedentes:
- El glucagón pancreático estimula la gluconeogénesis hepática a través del CRTC2 en mamíferos en ayunas.
- La obesidad está relacionada con el aumento de la producción hepática de glucosa y el estrés en el retículo endoplasmático (ER), lo que contribuye a la resistencia a la insulina.
Objetivo del estudio:
- Investigar si el estrés ER modula directamente el programa gluconeogénico.
- Para aclarar el papel de CRTC2 como un sensor para las señales de estrés ER y de ayuno.
Principales métodos:
- Investigó la interacción entre CRTC2 y ATF6alpha en respuesta al estrés ER.
- Utilizó la interferencia de ARN (RNAi) mediada por el derribo de ATF6alpha en ratones obesos.
- Se examinaron los efectos de la sobreexpresión de ATF6alpha en la producción hepática de glucosa y el programa gluconeogénico.
Principales resultados:
- El estrés de ER induce la desfosforilación y la entrada nuclear de CRTC2, promoviendo la expresión génica de control de calidad de ER a través de ATF6alpha.
- ATF6alpha interrumpe la interacción CREB-CRTC2, inhibiendo la ocupación de CRTC2 en los genes gluconeogénicos y reduciendo la producción de glucosa hepática.
- La reducción de los niveles hepáticos de ATF6alfa o el estrés ER persistente en la obesidad regulan al alza la producción de glucosa hepática.
Conclusiones:
- CRTC2 funciona como un sensor dual para las señales de estrés y de ayuno de ER.
- La interacción cruzada entre las vías de estrés ER y de ayuno, mediada por CRTC2 y ATF6alpha, es crucial para regular la producción hepática de glucosa y mantener la homeostasis de la glucosa.
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