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Un receptor de vitamina D/SMAD abre las puertas del circuito genómico de la respuesta fibrótica hepática
Ning Ding1, Ruth T Yu, Nanthakumar Subramaniam
1Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Cell
|April 30, 2013
Resumen
Los ligandos del receptor de vitamina D (VDR) inhiben la fibrosis hepática al bloquear la activación de las células estelares hepáticas. El VDR juega un papel crucial en la regulación de la cicatrización de heridas hepáticas y puede ofrecer una nueva terapia para la fibrosis hepática.
Área de la Ciencia:
- Hepatología Hepatología.
- Biología Molecular Biología Molecular
- Endocrinología Endocrinología.
Sus antecedentes:
- La fibrosis hepática es una respuesta patológica de cicatrización de heridas caracterizada por una deposición excesiva de la matriz extracelular.
- La activación de las células estelares hepáticas (HSC), impulsada por la señalización TGFβ1 / SMAD, es fundamental para la fibrosis hepática.
- El papel del receptor de vitamina D (VDR) en la fibrogénesis hepática no se entiende completamente.
Objetivo del estudio:
- Para investigar el papel de VDR en la activación de HSC y la fibrosis hepática.
- Para aclarar los mecanismos moleculares por los cuales VDR influye en la señalización TGFβ1 / SMAD en HSCs.
- Explorar el potencial terapéutico de los ligandos VDR en el tratamiento de la fibrosis hepática.
Principales métodos:
- Estudios in vitro con HSCs tratados con ligandos TGFβ1 y VDR.
- Estudios in vivo con ratones knockout Vdr y ratones de tipo salvaje.
- Secuenciación de inmunoprecipitación de cromatina (ChIP-seq) para mapear los sitios de unión VDR y SMAD3.
- Análisis de expresión génica para evaluar los marcadores profibróticos.
Principales resultados:
- Los ligandos del VDR inhibieron la activación del HSC inducida por TGFβ1 y la fibrosis hepática abrogada.
- Los ratones Vdr knockout exhibieron fibrosis hepática espontánea.
- La señalización de TGFβ1 alteró los sitios de unión de todo el genoma del VDR, promoviendo la interacción del VDR con los genes profibróticos.
- El tratamiento con ligandos VDR redujo la ocupación de SMAD3 en estos genes diana, inhibiendo así la fibrosis.
Conclusiones:
- El VDR actúa como un punto de control endocrino que modula la respuesta de cicatrización de heridas en el hígado.
- Un circuito genómico VDR/SMAD que se cruza regula la fibrogénesis hepática.
- Los ligandos VDR representan una estrategia terapéutica prometedora para la fibrosis hepática.
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