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Induction of an Inflammatory Response in Primary Hepatocyte Cultures from Mice
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CREB controla el metabolismo de los lípidos hepáticos a través del receptor de la hormona nuclear PPAR-gamma
Stephan Herzig1, Susan Hedrick, Ianessa Morantte
1Peptide Biology Laboratories Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037-1002, USA.
Nature
|November 14, 2003
Resumen
El ayuno suprime la síntesis de grasa mediante la activación de CREB, que inhibe el PPAR-gamma a través de HES-1. Este mecanismo explica la regulación de la grasa hepática durante el ayuno y sugiere objetivos terapéuticos para la sensibilidad a la insulina.
Área de la Ciencia:
- Regulación del metabolismo.
- Endocrinología Molecular La Endocrinología Molecular
- La señalización hormonal.
Sus antecedentes:
- El ayuno induce la producción de glucosa en el hígado y la descomposición de los lípidos a través de señales hormonales.
- La proteína de unión al elemento sensible a la cAMP (CREB) activa las vías de oxidación gluconeogénica y de los ácidos grasos.
- Los mecanismos que suprimen las vías lipogénicas hepáticas durante el ayuno siguen siendo en gran medida desconocidos.
Objetivo del estudio:
- Para dilucidar el mecanismo molecular por el cual el ayuno suprime la lipogénesis hepática.
- Investigar el papel de CREB y sus objetivos aguas abajo en la regulación del metabolismo lipídico durante el ayuno.
Principales métodos:
- Se utilizaron ratones con deficiencia de CREB para estudiar los fenotipos hepáticos.
- Expresión génica analizada de los receptores de hormonas nucleares (por ejemplo, PPAR-gamma) y los represores de la transcripción (por ejemplo, HES-1).
- Investigó el papel in vivo de HES-1 en el metabolismo lipídico inducido por el ayuno.
Principales resultados:
- Los ratones con deficiencia de CREB exhibieron un fenotipo de hígado graso con una elevada expresión de PPAR-gamma.
- Se encontró que CREB inhibe la expresión hepática de PPAR-gamma durante el ayuno al estimular HES-1.
- HES-1 actúa como mediador del metabolismo lipídico en ayunas in vivo.
Conclusiones:
- CREB coordina la inducción de PGC-1 y la represión de PPAR-gamma durante el ayuno.
- Esto proporciona una base molecular para la interacción entre la insulina y las hormonas contrarreguladoras.
- Los antagonistas de CREB pueden representar una estrategia terapéutica para mejorar la sensibilidad hepática a la insulina.
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