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Inicio Gastroenterología y Hepatología (English Edition) MicroRNA-378 inhibits hepatocyte apoptosis during acute liver failure by targeti...
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Vol. 46. Issue 2.
Pages 124-134 (February 2023)
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Vol. 46. Issue 2.
Pages 124-134 (February 2023)
Original Article
MicroRNA-378 inhibits hepatocyte apoptosis during acute liver failure by targeting caspase-9 in mice
MicroRNA-378 inhibe la apoptosis de los hepatocitos durante la insuficiencia hepática aguda al dirigirse a la caspasa-9 en ratones
Zhiwen Fenga, Shenghua Baoa, Lianbao Kongb, Xiaopeng Chena,
Corresponding author
qing20210528@163.com

Corresponding author.
a Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, China
b Department of Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Abstract
Background

Acute liver failure (ALF) is a severe and potentially lethal clinical syndrome. It has been demonstrated that micro ribonucleic acids (miRNAs) are crucial mediators of nearly all pathological processes, including liver disease.

Objective

The present study investigates the role of miR-378 in ALF. An ALF mouse model was induced using intraperitoneal injections of d-galactosamine/lipopolysaccharide (d-GalN/LPS). A hepatocyte cell line and miR-378 analogue were used in vitro to investigate the possible roles of miR-378 in ALF.

Methods

The expressions of miR-378 and predicted target genes were measured via reverse transcription-quantitative polymerase chain reaction and western blotting, and cell apoptosis was assayed using flow cytometry.

Results

Compared with mice in the control group, the mice challenged with d-GalN/LPS showed higher levels of alanine aminotransferase, aspartate aminotransferase, tumour necrosis factor-alpha and interleukin-6, more severe liver damage and increased numbers of apoptotic hepatocytes. Hepatic miR-378 was distinctly downregulated, while messenger RNA and protein levels of cysteinyl aspartate specific proteinase 9 (caspase-9) were upregulated in the ALF model. Furthermore, miR-378 was downregulated in d-GalN/TNF-induced hepatocyte cells, and miR-378 was found to inhibit hepatocyte apoptosis by targeting caspase-9.

Conclusion

Together, the present results indicate that miR-378 is a previously unrecognised post-ALF hepatocyte apoptosis regulator and may be a potential therapeutic target in the context of ALF.

Keywords:
miRNAs
Acute liver failure
Liver damage
Resumen
Antecedentes

La insuficiencia hepática aguda (ALF) es un síndrome clínico grave y potencialmente letal. Se ha demostrado que los microácidos ribonucleicos (miRNA) son mediadores cruciales de casi todos los procesos patológicos, incluida la enfermedad hepática.

Objetivo

El presente estudio investiga el papel de miR-378 en ALF. Se indujo ALF en un modelo de ratón usando inyecciones intraperitoneales de d-galactosamina/lipopolisacárido (d-GalN/LPS). Se utilizaron una línea celular de hepatocitos y un análogo de miR-378 in vitro para investigar las posibles funciones de miR-378 en ALF.

Métodos

Las expresiones de miR-378 y los genes diana predichos se midieron mediante la reacción en cadena de polimerasa cuantitativa con transcripción inversa y transferencia de Western, y la apoptosis celular se analizó mediante citometría de flujo.

Resultados

En comparación con los ratones del grupo de control, los ratones desafiados con d-GalN/LPS mostraron niveles más altos de alanina aminotransferasa, aspartato aminotransferasa, factor de necrosis tumoral alfa e interleucina-6, daño hepático más grave y un mayor número de hepatocitos apoptóticos. El miR-378 hepático se reguló claramente a la baja, mientras que el ARN mensajero y los niveles de proteína de la proteinasa 9 específica de aspartato de cisteinilo (caspasa-9) se regularon al alza en el modelo ALF. Además, miR-378 se reguló a la baja en las células de hepatocitos inducidas por d-GalN/TNF, y se descubrió que miR-378 inhibía la apoptosis de los hepatocitos al interferir en la transcripción de la caspasa-9.

Conclusión

Juntos, los presentes resultados indican que miR-378 es un regulador de la apoptosis de hepatocitos post-ALF previamente no reconocido y puede ser un objetivo terapéutico potencial en el contexto de ALF.

Palabras clave:
miARN
Insuficiencia hepática aguda
Daño hepático

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