Actividad Investigadora
Metabolic dysfunction-associated steatotic liver disease alters brain function and behavior: Insights from liver-targeted siRNA therapy.
Fecha de publicación:
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Autores de IDIVAL
Autores ajenos al IDIVAL
- Cardoso Delgado T
- Martín-Cuevas C
- Sánchez Hidalgo AC
- Gil Gómez A
- Rejano Gordillo CM
- Landa J
- Gallego Durán R
- Goikoetxea-Usandizaga N
- González-Recio I
- Gil-Pitarch C
- Zapata-Pavas LE
- Barrenechea-Barrenechea JA
- Conter C
- Martínez-Cruz LA
- Ramos Herrero VD
- Nogueiras R
- Azkargorta M
- Elortza F
- Moncho-Amor V
- Matheu A
- Romero Gómez M
- Crespo-Facorro B
Unidades
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD), a liver-centric condition, is associated with cognitive impairment and sensorimotor alterations. However, it remains unclear whether MASLD is sufficient to drive central nervous system deficits. Here, using diet-induced mouse models, we showed that MASLD was associated with alterations in social memory, sensorimotor processing, and hippocampal function, including decreased parvalbumin-positive interneurons, reduced dendritic spine density, and diminished dentate gyrus neurogenesis and neuronal differentiation. Then, we selectively modulated liver metabolism through N-acetylgalactosamine small interfering RNA (siRNA) therapy against Cyclin M4 (CNNM4), a magnesium transporter dysregulated in MASLD. Liver-specific intervention with siRNA-Cnnm4 reversed impaired social memory and sensorimotor processing in association with recovery of hippocampal synaptogenesis and mitochondrial function pathways, alongside activation of neurogenesis-associated transcriptional programs. Our findings demonstrate that liver pathology is sufficient to drive neurobehavioral and hippocampal dysfunction in MASLD. Hepatic-specific intervention restores brain function, strongly supporting the existence of a causal and therapeutically targetable liver-brain axis for MASLD-associated neurological complications.
Datos de la publicación
- ISSN/ISSNe:
- 2375-2548, 2375-2548
- Tipo:
- Article
- Páginas:
- -
- PubMed:
- 41124271
Science Advances AMER ASSOC ADVANCEMENT SCIENCE
Citas Recibidas en Web of Science: 2
Documentos
- No hay documentos
Filiaciones
Campos de Estudio
Proyectos asociados
Dianas terapéuticas y biomarcadores para la medicina de precisión en MAFLD (PreMed-MAFLD)
Investigador Principal: Javier Crespo García
PMP21/00112 . INSTITUTO DE SALUD CARLOS III. . 2022
Cita
Cardoso T, Martín C, Sánchez AC, Gil A, Rejano CM, Landa J, Gallego R, Goikoetxea N, González I, Gil C, Zapata LE, Barrenechea JA, Conter C, Martínez LA, Ramos VD, Nogueiras R, Azkargorta M, Elortza F, Moncho V, Crespo J, Matheu A, Romero M, Crespo B, Martínez ML. Metabolic dysfunction-associated steatotic liver disease alters brain function and behavior: Insights from liver-targeted siRNA therapy. Sci. Adv. 2025. 11. (43):eady9758. IF:12,500. (1).
