El estrés ER impulsa la lipogénesis y la esteatohepatitis a través de la activación de la caspasa-2 de S1P
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An Advanced Murine Model for Nonalcoholic Steatohepatitis in Association with Type 2 Diabetes
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Ju Youn Kim1, Ricard Garcia-Carbonell1, Shinichiro Yamachika1
1Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California San Diego, School of Medicine, La Jolla, CA 92093, USA.
Cell
|September 18, 2018
Resumen
La activación de la caspasa-2 impulsa la progresión de la enfermedad hepática grasa no alcohólica (NAFLD) a la esteatohepatitis no alcohólica (NASH) mediante el aumento del colesterol libre. La inhibición de la caspasa-2 previene el desarrollo de la NASH, ofreciendo una estrategia terapéutica potencial.
Área de la Ciencia:
- Hepatología
- Biología molecular
- La bioquímica
Sus antecedentes:
- La enfermedad hepática grasa no alcohólica (NAFLD) puede progresar a esteatohepatitis no alcohólica (NASH) debido al estrés del retículo endoplasmático (ER).
- La progresión de la NASH está relacionada con la acumulación de colesterol libre en los hepatocitos, a diferencia de la esteatosis simple que implica la lipogénesis de novo.
Objetivo del estudio:
- Investigar el papel de la caspasa-2 en la acumulación de colesterol y triglicéridos libres hepáticos durante la progresión de la EHNA.
- Para explorar la caspasa-2 como un potencial objetivo terapéutico y biomarcador para la EHNA.
Principales métodos:
- Expresión examinada de la caspasa-2 en modelos de NASH en humanos y ratones.
- Se investigó la interacción de la caspasa-2 con la proteasa del sitio 1 (S1P) y su efecto sobre las proteínas reguladoras de esteroles (SREBP).
- Utilizó la ablación de la caspasa-2 y la inhibición farmacológica en modelos de NASH inducidos por la dieta.
Principales resultados:
- La expresión de la caspasa-2 es inducible por el estrés ER y elevada en la NASH.
- Caspase-2 activa SREBP1/ 2 independientemente de SCAP mediante la escisión de S1P, lo que lleva a la acumulación de colesterol y triglicéridos.
- La inhibición de la caspasa-2 evitó la esteatosis inducida por la dieta y la progresión de la NASH en ratones.
Conclusiones:
- La caspasa-2 juega un papel crítico en la conducción de la progresión de la NASH mediante el control de los niveles de colesterol libre y triglicéridos hepáticos.
- La inhibición de la caspasa-2 es una estrategia prometedora para el tratamiento o la prevención de enfermedades del hígado graso inducidas por el estrés.
- Los fragmentos de S1P generados por la caspasa-2 son biomarcadores potenciales para la EHNA.
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