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Dirigirse a HMGCS2: La supresión de la cetogénesis acelera la progresión de la EHGNA en la comorbilidad T2DM,
Yongsheng Shu1, Wanqing Shen1, Wanyu Feng1
1Department of Pharmacology, School of Pharmacy, Wannan Medical College, Wuhu 241002, China.
Biomolecules
|August 28, 2025
Resumen
La desregulación de la cetogénesis empeora la enfermedad hepática grasa no alcohólica (EHGNA) en la diabetes tipo 2. La mejora de la cetogénesis con cinarosida ofrece una estrategia terapéutica para esta condición compleja.
Área de la Ciencia:
- Hepatología
- Endocrinología
- Enfermedades metabólicas
Sus antecedentes:
- La enfermedad hepática grasa no alcohólica (NAFLD) y la diabetes mellitus tipo 2 (DMT2) aceleran el daño hepático, aumentando los riesgos de cirrosis y cáncer.
- La cetogénesis, la producción de cuerpos cetónicos, juega un papel en la regulación metabólica y puede alterarse en la NAFLD asociada a la DM2.
Objetivo del estudio:
- Investigar el papel de la cetogénesis en la exacerbación de la NAFLD mediada por la DM2.
- Para aclarar el mecanismo terapéutico de la cinarosida en la esteatohepatitis no alcohólica (NASH) complicada por DM2.
Principales métodos:
- Se ha comprobado la presencia de NAFLD con modelos de DMT2 en ratones que han utilizado CDAHFD y estreptozotocina.
- Expresión hepática modulada de HMGCS2 a través de vectores adenovirales para la sobreexpresión o el knockdown.
- Se administró cinarosida por vía oral y se analizaron los marcadores de patología hepática, cetogénesis y senescencia.
Principales resultados:
- La DM2 aceleró la progresión de la EHGNA, relacionada con la cetogénesis desregulada y la expresión hepática de HMGCS2.
- La sobreexpresión de HMGCS2 atenuó la esteatohepatitis en los modelos NASH-T2DM mediante el aumento de la cetogénesis.
- Cynaroside mejoró la lesión hepática, redujo la acumulación de lípidos y suprimió la senescencia hepatocítica y los factores SASP.
Conclusiones:
- La desregulación cetogénica mediada por HMGCS2 contribuye a la patogénesis de la EHGNA en el DM2.
- La cinarosida ejerce efectos terapéuticos en la NASH-T2DM a través de la cetogénesis mediada por HMGCS2.
- La modulación cetogénica representa una estrategia terapéutica prometedora para retrasar la progresión de la DM2NAFLD.
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