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Los receptores nucleares sensibles a los nutrientes también coordinan la autofagia
Jae Man Lee1, Martin Wagner1, Rui Xiao1
1Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Nature
|November 11, 2014
Resumen
Los receptores de nutrientes PPARα y FXR controlan la autofagia hepática. PPARα promueve la autofagia en estados de alimentación, mientras que FXR la suprime en estados de ayuno, revelando mecanismos clave de regulación transcripcional.
Área de la Ciencia:
- Biología celular Biología celular.
- El metabolismo es el metabolismo.
- Endocrinología Molecular La Endocrinología Molecular
Sus antecedentes:
- La autofagia es un proceso conservado para el reciclaje de nutrientes y la homeostasis energética.
- Si bien se comprende la regulación aguda de la autofagia, su control transcripcional a largo plazo sigue sin estar claro.
- Los receptores nucleares PPARα (hígado en ayunas) y FXR (hígado alimentado) son sensores de nutrientes clave.
Objetivo del estudio:
- Para investigar las funciones de PPARα y FXR en la regulación transcripcional de la autofagia hepática en ratones.
- Para dilucidar cómo estos receptores nucleares modulan la autofagia en respuesta al estado de los nutrientes (ayuno frente a la alimentación).
Principales métodos:
- Utilizó la activación farmacológica de PPARα y FXR en ratones de tipo salvaje.
- Empleó modelos de ratones knockout (Ppara(-/-) y Fxr(-/-)) para evaluar las funciones funcionales.
- Analizó la regulación transcripcional mediante el examen de la unión al promotor y la expresión génica relacionada con la autofagia.
Principales resultados:
- La activación de PPARα revirtió la supresión de la autofagia en el estado alimentado, induciendo la lipofagia, una respuesta ausente en ratones Ppara.
- La activación de la FXR suprimió la inducción de la autofagia en ayunas, una respuesta ausente en los ratones Fxr{-/-}.
- Se encontró que PPARα y FXR compiten por la unión a promotores de genes autofágicos compartidos, ejerciendo efectos transcripcionales opuestos.
Conclusiones:
- PPARα y FXR son reguladores críticos de la autofagia hepática, que responden a la disponibilidad de nutrientes.
- Estos receptores proporcionan mecanismos transcripcionales complementarios e interconectados para controlar la autofagia en función del estado nutricional.
- Los hallazgos revelan nuevos conocimientos sobre la regulación a largo plazo de la autofagia más allá de las vías de señalización aguda.
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